CN112125901A - Inhibitors of lysine-specific demethylase-1 - Google Patents

Abstract

The present application relates to inhibitors of lysine-specific demethylase-1. The present application generally relates to compositions and methods for treating cancer and neoplastic diseases. Provided herein are Substituted Heterocyclic Derivative Compounds and pharmaceutical compositions comprising the same. The subject compounds and compositions are useful for inhibiting lysine-specific demethylase-1. In addition, the subject compounds and compositions are useful for the treatment of cancers such as prostate cancer, breast cancer, bladder cancer, lung cancer and/or melanoma and the like.

Description

Inhibitors of lysine-specific demethylase-1

This application is a divisional application of an application with an application date of September 3, 2015, an application number of 201580059765.5, and an invention title of "Inhibitor of Lysine-Specific Demethylase-1".

cross reference

This application claims the benefit of US Provisional Application No. 62/046,842, filed September 5, 2014, the entire contents of which are hereby incorporated by reference.

technical field

The present application relates generally, but is not limited to, inhibitors of lysine-specific demethylase-1.

background

There is a need in the art for effective treatment of cancer and neoplastic diseases.

Brief description of the invention

Provided herein are Substituted Heterocyclic Derivative Compounds and pharmaceutical compositions comprising the same. The subject compounds and compositions are useful for inhibiting lysine specific demethylase-1 (LSD-1). In addition, the subject compounds and compositions are useful for the treatment of cancers such as prostate cancer, breast cancer, bladder cancer, lung cancer and/or melanoma and the like. The substituted heterocyclic derivative compounds described herein are based on a central heterocyclic ring system such as pyrazine, 4-azaindazole, 4-azaindazole, pyrimidine or Pyrazole or similar. The central heterocyclic ring system is further substituted with a 4-cyanophenyl group and a heterocyclyl group.

One embodiment provides a compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof,

in,

X and Y are each independently selected from CH, CF, C _- CH or N;

Z is selected from C-H or N;

R is selected from hydrogen, halogen, aryl, heteroaryl, heterocyclyl, carbocyclyl, alkoxy, cycloalkylalkoxy or aralkoxy;

W is -L-G, heterocyclyl or heteroaryl;

L is an alkylene group;

G is -N(R ¹ ) ₂ , heterocyclyl or heteroaryl; and

R ¹ is hydrogen or alkyl.

One embodiment provides a compound having the structure of formula (II), or a pharmaceutically acceptable salt thereof,

in,

X and Y are each independently selected from CH, CF, C _- CH or N;

W is selected from CH, CF, C-Cl, C- _CH3 , C- _CF3 , C- _OCH3 , C _{- OCH2CH3} , or N;

Z is selected from -G, -CH ₂ -G, -CH ₂ -CH ₂ -G, -N(R ¹ )-G, -N(R ¹ )-CH ₂ -G, -OG, -O-CH ₂ -G or -C(O)N(R ² )(R ³ );

G is carbocyclyl, aryl, heterocyclyl or heteroaryl;

R ¹ is hydrogen or alkyl;

R2 and ^R3 are independently selected from ^hydrogen , alkyl, heterocyclyl, heterocyclylalkyl, or optionally, R2 and ^R3 are linked to form an N ^- linked heterocyclyl ring system;

R is selected from aryl, halogen, heteroaryl, heterocyclyl, carbocyclyl, alkoxy, cycloalkylalkoxy or aralkoxy.

One embodiment provides a compound having the structure of formula (III), or a pharmaceutically acceptable salt thereof,

in,

X and Y are each independently selected from CH, CF, C _- CH or N;

Z is selected from -G, -CH ₂ -G, -CH ₂ -CH ₂ -G, -N(R ¹ )-G, -N(R ¹ )-CH ₂ -G, -OG, -O-CH ₂ -G or -C(O)N(R ² )(R ³ );

G is carbocyclyl, aryl, heterocyclyl or heteroaryl;

R ¹ is hydrogen or alkyl;

R2 and ^R3 are independently selected from ^hydrogen , alkyl, heterocyclyl, heterocyclylalkyl, or optionally, R2 and ^R3 are linked to form an N ^- linked heterocyclyl ring system;

R is selected from alkoxy, carbocyclylalkoxy, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, alkynyl or carbocyclylalkynyl.

One embodiment provides a compound having the structure of formula (IV) or a pharmaceutically acceptable salt thereof,

in,

X and Y are each independently selected from CH, CF, C _- CH or N;

Z is selected from -G, -CH ₂ -G, -CH ₂ -CH ₂ -G, -N(R ¹ )-G, -N(R ¹ )-CH ₂ -G, -OG, -O-CH ₂ -G or -C(O)N(R ² )(R ³ );

X ¹ , X ² , and X ³ are each independently selected from N or CR ⁴ ; provided that at least one of X ¹ , X ² or X ³ is N;

G is carbocyclyl, aryl, heterocyclyl or heteroaryl;

R ¹ is hydrogen or alkyl;

R2 and ^R3 are independently selected from ^hydrogen , alkyl, heterocyclyl, heterocyclylalkyl, or optionally, R2 and ^R3 are linked to form an N ^- linked heterocyclyl ring system;

R ⁴ is hydrogen, halogen, C ₁ -C ₃ alkyl or C ₁ -C ₃ alkoxy; and

R is aryl, heteroaryl, alkynyl or cycloalkylalkynylene.

One embodiment provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

One embodiment provides a pharmaceutical composition comprising a compound of formula (II), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

One embodiment provides a pharmaceutical composition comprising a compound of formula (III), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

One embodiment provides a pharmaceutical composition comprising a compound of formula (IV), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

One embodiment provides a method of modulating gene transcription in a cell, the method comprising inhibiting a lysine-specific demethylase 1 enzyme by exposing the lysine-specific demethylase 1 enzyme to a compound of formula (I) 1 active.

One embodiment provides a method of modulating gene transcription in a cell, the method comprising inhibiting a lysine-specific demethylase 1 enzyme by exposing the lysine-specific demethylase 1 enzyme to a compound of formula (II) 1 active.

One embodiment provides a method of modulating gene transcription in a cell, the method comprising inhibiting a lysine-specific demethylase 1 enzyme by exposing the lysine-specific demethylase 1 enzyme to a compound of formula (III) 1 active.

One embodiment provides a method of modulating gene transcription in a cell, the method comprising inhibiting a lysine-specific demethylase 1 enzyme by exposing the lysine-specific demethylase 1 enzyme to a compound of formula (IV) 1 active.

One embodiment provides a method of treating cancer in a patient in need thereof, the method comprising administering to the patient a compound of formula (I) or a pharmaceutically acceptable salt thereof.

One embodiment provides a method of treating cancer in a patient in need thereof, the method comprising administering to the patient a compound of formula (II) or a pharmaceutically acceptable salt thereof.

One embodiment provides a method of treating cancer in a patient in need thereof, the method comprising administering to the patient a compound of formula (III) or a pharmaceutically acceptable salt thereof.

One embodiment provides a method of treating cancer in a patient in need thereof, the method comprising administering to the patient a compound of formula (IV) or a pharmaceutically acceptable salt thereof.

This application provides the following:

1). A compound having the structure of formula (IV) or a pharmaceutically acceptable salt thereof,

in,

X and Y are each independently selected from CH, CF, C _- CH or N;

Z is selected from -G, -CH ₂ -G, -CH ₂ -CH ₂ -G, -N(R ¹ )-G, -N(R ¹ )-CH ₂ -G, -OG, -O-CH ₂ -G or -C(O)N(R ² )(R ³ );

X ¹ , X ² and X ³ are each independently selected from N or CR ⁴ ; provided that at least one of X ¹ , X ² or X ³ is N;

G is carbocyclyl, aryl, heterocyclyl or heteroaryl;

R ¹ is hydrogen or alkyl;

R2 and ^R3 are independently selected from ^hydrogen , alkyl, heterocyclyl, heterocyclylalkyl, or optionally, R2 and ^R3 are linked to form an N ^- linked heterocyclyl ring system;

R ⁴ is hydrogen, halogen, C ₁ -C ₃ alkyl or C ₁ -C ₃ alkoxy; and

R is aryl, heteroaryl, alkynyl or cycloalkylalkynylene.

2). The compound of 1) or a pharmaceutically acceptable salt thereof, wherein R is aryl or heteroaryl.

3). The compound of 1) or 2) or a pharmaceutically acceptable salt thereof, wherein formula (IV) is formula (IVa):

4). The compound of 1) or 2) or a pharmaceutically acceptable salt thereof, wherein formula (IV) is formula (IVb):

5). The compound of 1) or 2) or a pharmaceutically acceptable salt thereof, wherein formula (IV) is formula (IVc):

6). The compound of 1) or 2) or a pharmaceutically acceptable salt thereof, wherein formula (IV) is formula (IVd):

7). The compound of 1) or 2) or a pharmaceutically acceptable salt thereof, wherein formula (IV) is formula (IVe):

8). The compound of 1) or 2) or a pharmaceutically acceptable salt thereof, wherein formula (IV) is formula (IVf):

9). The compound of 1) or 2) or a pharmaceutically acceptable salt thereof, wherein formula (IV) is formula (IVg):

10). The compound of any one of 1)-9), or a pharmaceutically acceptable salt thereof, wherein X is C-H.

11). The compound of any one of 1)-9), or a pharmaceutically acceptable salt thereof, wherein X is C-F.

12). The compound of any one of 1) to 9), or a pharmaceutically acceptable salt thereof, wherein X is C-CH ₃ .

13). The compound of any one of 1)-9), or a pharmaceutically acceptable salt thereof, wherein X is N.

14). The compound of any one of 1)-9), or a pharmaceutically acceptable salt thereof, wherein Y is C-H.

15). The compound of any one of 1)-9), or a pharmaceutically acceptable salt thereof, wherein Y is C-F.

16). The compound of any one of 1) to 9), or a pharmaceutically acceptable salt thereof, wherein Y is C-CH ₃ .

17). The compound of any one of 1)-9), or a pharmaceutically acceptable salt thereof, wherein Y is N.

18). The compound or pharmaceutically acceptable salt of any one of 1)-9), wherein X is C-H and Y is C-H.

19). The compound of any one of 1) to 18), or a pharmaceutically acceptable salt thereof, wherein Z is -O- _CH2 -G.

20). The compound of any one of 1) to 18), or a pharmaceutically acceptable salt thereof, wherein Z is -O-G.

21). The compound of any one of 1) to 18), or a pharmaceutically acceptable salt thereof, wherein Z is -N(R ¹ )-CH ₂ -G.

22). The compound of any one of 1) to 18), or a pharmaceutically acceptable salt thereof, wherein Z is -N(R ¹ )-G.

23). The compound of any one of 1) to 18), or a pharmaceutically acceptable salt thereof, wherein Z is -CH ₂ -CH ₂ -G.

24). The compound of any one of 1) to 18), or a pharmaceutically acceptable salt thereof, wherein Z is _-CH2 -G.

25). The compound of any one of 1)-18), or a pharmaceutically acceptable salt thereof, wherein Z is -G.

26). The compound of any one of 1) to 18), or a pharmaceutically acceptable salt thereof, wherein Z is -C(O)N(R ² )(R ³ ).

27). The compound of 26), or a pharmaceutically acceptable salt thereof, wherein R ² and R ³ are independently selected from hydrogen or alkyl.

28). The compound of 26), or a pharmaceutically acceptable salt thereof, wherein R ² and R ³ are independently selected from heterocyclyl or heterocyclylalkyl.

29). The compound of 26), or a pharmaceutically acceptable salt thereof, wherein R ² and R ³ are linked to form an N-linked heterocyclyl ring system.

30). The compound of 21) or 22) or ^a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen.

31). The compound of 21) or 22) or a pharmaceutically acceptable salt thereof, wherein R ¹ is an alkyl group.

32). The compound of any one of 1)-8) or ¹⁰ )-31), or a pharmaceutically acceptable salt thereof, wherein R4 is hydrogen.

33). The compound of any one of 1)-8) or 10)-31), or a pharmaceutically acceptable salt thereof, wherein R ⁴ is C ₁ -C ₃ alkoxy.

34). The compound according to any one of 1)-25) or 30)-33), or a pharmaceutically acceptable salt thereof, wherein G is heterocyclyl.

35). The compound of any one of 1) to 34), or a pharmaceutically acceptable salt thereof, wherein G is a nitrogen-containing heterocyclyl group.

36). The compound of 35) or a pharmaceutically acceptable salt thereof, wherein the nitrogen-containing heterocyclic group is a five-membered heterocyclic group or a six-membered heterocyclic group.

37). The compound of 35) or a pharmaceutically acceptable salt thereof, wherein the heterocyclic group is selected from:

38). The compound of any one of 1) to 37), or a pharmaceutically acceptable salt thereof, wherein R is heteroaryl.

39). The compound of 38) or a pharmaceutically acceptable salt thereof, wherein R is a monocyclic nitrogen-containing heteroaryl.

40). The compound of 38) or a pharmaceutically acceptable salt thereof, wherein R is a bicyclic nitrogen-containing heteroaryl.

41). The compound of 40) or a pharmaceutically acceptable salt thereof, wherein R is selected from:

42). The compound of any one of 1) to 37), or a pharmaceutically acceptable salt thereof, wherein R is aryl.

43). The compound of 42), or a pharmaceutically acceptable salt thereof, wherein the aryl group is an optionally substituted phenyl group.

44). The compound of 42) or a pharmaceutically acceptable salt thereof, wherein the optionally substituted phenyl group is selected from 4-methylphenyl, 4-chlorophenyl, 4-fluoro phenyl, 4-cyanophenyl, 4-(methylsulfonyl)phenyl or 4-trifluoromethylphenyl.

45). The compound of 42) or a pharmaceutically acceptable salt thereof, wherein the optionally substituted phenyl group is selected from 4-methoxyphenyl, 3-fluoro-4-methoxy phenyl or 3-chloro-4-methoxyphenyl.

46). The compound of ⁵ ), or a pharmaceutically acceptable salt thereof, wherein X is CF, Y is CH and R4 is hydrogen.

47). The compound of 46) or a pharmaceutically acceptable salt thereof, wherein R is a bicyclic nitrogen-containing heteroaryl.

48). The compound of 47) or a pharmaceutically acceptable salt thereof, wherein R is selected from:

49). The compound of 47) or a pharmaceutically acceptable salt thereof, wherein R is selected from:

50). The compound of any one of 46)-49) or a pharmaceutically acceptable salt thereof, wherein

where G is

51). A pharmaceutical composition comprising a compound of formula (IV), or a pharmaceutically acceptable salt thereof, as described in any one of 1)-50), and a pharmaceutically acceptable excipient.

52). A method of modulating gene transcription in a cell, comprising by exposing a lysine-specific demethylase 1 enzyme to a compound of formula (IV) as described in any one of 1)-50) Inhibits lysine-specific demethylase 1 activity.

53). A method of treating cancer in a patient in need thereof, comprising administering a pharmaceutical composition comprising a compound of formula (IV) as described in any of 1)-50).

incorporated by reference

All publications, patents, and patent applications mentioned in this specification are incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference This article.

Detailed description of the invention

As used herein and in the appended claims, the singular forms "a (a)," "an (an)," and "the (the)" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an agent" includes a plurality of such agents, and reference to "the cell" includes reference to one or more cells known to those skilled in the art (or multiple cells mentioned) and their equivalents, etc. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, it is intended to include all combinations and subcombinations of ranges as well as specific embodiments therein. The term "about" when referring to a number or range of values means that the number or range of values referred to is an approximation within experimental variability (or within statistical experimental error) and therefore the number or Numerical ranges may vary between 1% and 15% of the stated numbers or numerical ranges. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") is not intended to exclude certain other embodiments For example, in any of the compositions of matter embodiments, the compositions, methods or processes, or the like, described herein may be "consisting of" or "consisting essentially of the described features."

definition

As used in this specification and the appended claims, unless specified to the contrary, the following terms have the meanings indicated below.

"Amino" refers to the _-NH2 group.

"Cyano" refers to the -CN group.

"Nitro" refers to the -NO ₂ group.

"Oxa" refers to the -O- group.

"Oxo" refers to the =O group.

"Thio" refers to the =S group.

"Imino" refers to a =N-H group.

"Oximino" refers to a =N-OH group.

"hydrazino" refers to the =N- _NH2 group.

"Alkyl" refers to a straight or branched hydrocarbon chain group consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to fifteen carbon atoms (eg, C ₁ -C ₁₅ alkyl). In certain embodiments, the alkyl group contains one to thirteen carbon atoms (eg, C ₁ -C ₁₃ alkyl). In certain embodiments, the alkyl group contains one to _eight carbon atoms (eg, _C1 -C8 alkyl). In other embodiments, the alkyl group contains one to five carbon atoms (eg, _C1 - _C5 alkyl). In other embodiments, the alkyl group contains one to four carbon atoms (eg, _C1 - _C4 alkyl). In other embodiments, the alkyl group contains one to three carbon atoms (eg, _{C1 -} C3 alkyl). In other embodiments, the alkyl group contains one to two carbon atoms (eg, _C1 - _C2 alkyl). In other embodiments, the alkyl group contains one carbon atom (eg, _C1 alkyl). In other embodiments, the alkyl group contains five to fifteen carbon atoms (eg, _C5 - _C15 alkyl). In other embodiments, the alkyl group contains five to _eight carbon atoms (eg, _C5 -C8 alkyl). In other embodiments, the alkyl group contains two to five carbon atoms (eg, C2 _{- C5} alkyl). In other embodiments, the alkyl group contains three to five carbon atoms (eg, C3 _{- C5} alkyl). In other embodiments, the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (isopropyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl), 1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl). The alkyl group is attached to the remainder of the molecule through a single bond. Unless specifically stated otherwise in this specification, alkyl groups are optionally substituted with one or more of the following substituents: halogen, cyano, nitro, oxo, thio, imino, oximo , trimethylsilyl, -OR ^a , -SR ^a , -OC(O)-R ^a , -N(R ^a ) ₂ , -C(O)R ^a , -C(O)OR ^a , -C (O)N(R ^a ) ₂ , -N(R ^a )C(O)OR ^a , -OC(O)-N(R ^a ) ₂ , -N(R ^a )C(O)R ^a , - N(R ^a )S(O) _t R ^a (where t is 1 or 2), -S(O) _t OR ^a (where t is 1 or 2), -S(O) _t R ^a (where t is 1 or 2) and -S(O) _t N(R ^a ) ₂ (wherein t is 1 or 2), wherein each R ^a is independently hydrogen, alkyl (optionally replaced by halogen, hydroxy, methoxy , or trifluoromethyl substituted), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy , methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methyl) oxy, or trifluoromethyl substituted).

"Alkoxy" refers to a group bonded through an oxygen atom of the formula -O-alkyl, where alkyl is an alkyl chain as defined above.

"Alkenyl" refers to a straight or branched hydrocarbon chain group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms . In certain embodiments, the alkenyl group contains two to eight carbon atoms. In other embodiments, the alkenyl group contains two to four carbon atoms. The alkenyl group is attached to the rest of the molecule through a single bond, such as ethenyl (ie, vinyl), prop-1-enyl (ie, allyl), but-1-enyl , pent-1-enyl, pent-1,4-dienyl, and similar alkenyl groups. Unless specifically stated otherwise in this specification, alkenyl groups are optionally substituted with one or more of the following substituents: halogen, cyano, nitro, oxo, thio, imino, oximo , trimethylsilyl, -OR ^a , -SR ^a , -OC(O)-R ^a , -N(R ^a ) ₂ , -C(O)R ^a , -C(O)OR ^a , -C (O)N(R ^a ) ₂ , -N(R ^a )C(O)OR ^a , -OC(O)-N(R ^a ) ₂ , -N(R ^a )C(O)R ^a , - N(R ^a )S(O) _t R ^a (where t is 1 or 2), -S(O) _t OR ^a (where t is 1 or 2), -S(O) _t R ^a (where t is 1 or 2) and -S(O) _t N(R ^a ) ₂ (wherein t is 1 or 2), wherein each R ^a is independently hydrogen, alkyl (optionally replaced by halogen, hydroxy, methoxy , or trifluoromethyl substituted), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy , methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methyl) oxy, or trifluoromethyl substituted).

"Alkynyl" refers to a straight or branched hydrocarbon chain group consisting solely of carbon atoms and hydrogen atoms, containing at least one carbon-carbon triple bond, having from two to twelve carbon atoms. In certain embodiments, the alkynyl group contains two to eight carbon atoms. In other embodiments, the alkynyl group contains two to six carbon atoms. In other embodiments, the alkynyl group contains two to four carbon atoms. Alkynyl groups are attached to the remainder of the molecule through a single bond, such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, and similar alkynyl groups. Unless specifically stated otherwise in this specification, alkynyl groups are optionally substituted with one or more of the following substituents: halogen, cyano, nitro, oxo, thio, imino, oximo , trimethylsilyl, -OR ^a , -SR ^a , -OC(O)-R ^a , -N(R ^a ) ₂ , -C(O)R ^a , -C(O)OR ^a , -C (O)N(R ^a ) ₂ , -N(R ^a )C(O)OR ^a , -OC(O)-N(R ^a ) ₂ , -N(R ^a )C(O)R ^a , - N(R ^a )S(O) _t R ^a (where t is 1 or 2), -S(O) _t OR ^a (where t is 1 or 2), -S(O) _t R ^a (where t is 1 or 2) and -S(O) _t N(R ^a ) ₂ (wherein t is 1 or 2), wherein each R ^a is independently hydrogen, alkyl (optionally replaced by halogen, hydroxy, methoxy , or trifluoromethyl substituted), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy , methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methyl) oxy, or trifluoromethyl substituted).

"Alkylene" or "alkylene chain" refers to a straight line consisting solely of carbon and hydrogen, containing no unsaturation, and having from one to twelve carbon atoms attaching the remainder of the molecule to the group Chained or branched divalent hydrocarbon chains such as methylene, ethylene, propylene, n-butylene, and similar alkylene groups. The alkylene chain is attached to the remainder of the molecule by a single bond and to the group by a single bond. The point of attachment of the alkylene chain to the remainder of the molecule and to the group can be through one carbon in the alkylene chain or through any two carbons within the chain. In certain embodiments, an alkylene group contains one to _eight carbon atoms (eg, _C1 -C8 alkylene). In other embodiments, the alkylene group contains one to five carbon atoms (eg, _C1 - _C5 alkylene). In other embodiments, the alkylene group contains one to four carbon atoms (eg, _C1 - _C4 alkylene). In other embodiments, the alkylene group contains one to three carbon atoms (eg, _{C1 -} C3 alkylene). In other embodiments, the alkylene group contains one to two carbon atoms (eg, _{C1 -} C2 alkylene). In other embodiments, the alkylene group contains one carbon atom (eg, a _C1 alkylene group). In other embodiments, the alkylene group contains five to _eight carbon atoms (eg, _C5 -C8 alkylene). In other embodiments, the alkylene group contains two to five carbon atoms (eg, C2 _{- C5} alkylene). In other embodiments, the alkylene group contains three to five carbon atoms (eg, C3 _{- C5} alkylene). Unless specifically stated otherwise in this specification, the alkylene chain is optionally substituted with one or more of the following substituents: halogen, cyano, nitro, oxo, thio, imino, oximo , trimethylsilyl, -OR ^a , -SR ^a , -OC(O)-R ^a , -N(R ^a ) ₂ , -C(O)R ^a , -C(O)OR ^a , -C (O)N(R ^a ) ₂ , -N(R ^a )C(O)OR ^a , -OC(O)-N(R ^a ) ₂ , -N(R ^a )C(O)R ^a , - N(R ^a )S(O) _t R ^a (where t is 1 or 2), -S(O) _t OR ^a (where t is 1 or 2), -S(O) _t R ^a (where t is 1 or 2) and -S(O) _t N(R ^a ) ₂ (wherein t is 1 or 2), wherein each R ^a is independently hydrogen, alkyl (optionally replaced by halogen, hydroxy, methoxy , or trifluoromethyl substituted), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy , methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methyl) oxy, or trifluoromethyl substituted).

"Alkynylene" or "alkynylene chain" refers to a chain consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond, and having from two to twelve carbon atoms linking the remainder of the molecule to A linear or branched divalent hydrocarbon chain of a group. The alkynylene chain is attached to the remainder of the molecule by a single bond and to the group by a single bond. In certain embodiments, an alkynylene group contains two to _eight carbon atoms (eg, C2 _- C8 alkynylene). In other embodiments, the alkynylene group contains two to five carbon atoms (eg, C2 _{- C5} alkynylene). In other embodiments, the alkynylene group contains two to _four carbon atoms (eg, C2 _- C4alkynylene). In other embodiments, the alkynylene group contains two to _three carbon atoms (eg, C2 _- C3 alkynylene). In other embodiments, the alkynylene group contains two carbon atoms (eg, C ₂ alkynylene). In other embodiments, the alkynylene group contains five to _eight carbon atoms (eg, _C5 -C8 alkynylene). In other embodiments, the alkynylene group contains three to five carbon atoms (eg, C3 _{- C5} alkynylene). Unless specifically stated otherwise in this specification, the alkynylene chain is optionally substituted with one or more of the following substituents: halogen, cyano, nitro, oxo, thio, imino, oximo , trimethylsilyl, -OR ^a , -SR ^a , -OC(O)-R ^a , -N(R ^a ) ₂ , -C(O)R ^a , -C(O)OR ^a , -C (O)N(R ^a ) ₂ , -N(R ^a )C(O)OR ^a , -OC(O)-N(R ^a ) ₂ , -N(R ^a )C(O)R ^a , - N(R ^a )S(O) _t R ^a (where t is 1 or 2), -S(O) _t OR ^a (where t is 1 or 2), -S(O) _t R ^a (where t is 1 or 2) and -S(O) _t N(R ^a ) ₂ (wherein t is 1 or 2), wherein each R ^a is independently hydrogen, alkyl (optionally replaced by halogen, hydroxy, methoxy , or trifluoromethyl substituted), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy , methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methyl) oxy, or trifluoromethyl substituted).

"Aryl" refers to a group derived from an aromatic monocyclic or polycyclic hydrocarbon ring system by removal of hydrogen atoms from ring carbon atoms. Aromatic monocyclic or polycyclic hydrocarbon ring systems contain only hydrogen and carbons from five to eighteen carbon atoms, wherein at least one of the rings in the ring system is completely unsaturated, i.e. according to the Hückel theory. ), which contains a cyclic, delocalized (4n+2)π electron system. Ring systems from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indene, indene, tetralin, and naphthalene. Unless specifically stated otherwise in this specification, the term "aryl" or the prefix "ar-" (such as in "aralkyl") is meant to include one or More substituent substituted aryl groups: alkyl, alkenyl, alkynyl, halogen, fluoroalkyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkane optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted Heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, ^-Rb - ^ORa , ^-Rb -OC (O)-R ^a , -R ^b -OC(O)-OR ^a , -R ^b -OC(O)-N(R ^a ) ₂ , -R ^b -N(R ^a ) ₂ , -R ^b - C(O)R ^a , -R ^b -C(O)OR ^a , -R ^b -C(O)N(R ^a ) ₂ , -R ^b -OR ^c -C(O)N(R ^a ) ₂ , -R ^b -N(R ^a )C(O)OR ^a , -R ^b -N(R ^a )C(O)R ^a , -R ^b -N(R ^a )S(O) _t R ^a ( where t is 1 or 2), -R ^b -S(O) _t R ^a (where t is 1 or 2), -R ^b -S(O) _t OR ^a (where t is 1 or 2) and -R ^b -S(O) _tN (R ^a ) ₂ (wherein t is 1 or 2), wherein each R ^a is independently hydrogen, alkyl (optionally halo, hydroxy, methoxy, or trifluoro) methyl substituted), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, , or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) fluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) fluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl substituted), each R is independently ^a direct bond or a straight or branched alkylene or ^alkenylene chain, and R is a straight or branched An alkyl chain or an alkenylene chain, and wherein each of the above substituents is unsubstituted unless otherwise indicated.

"Aralkyl" refers to a group of formula ^-Rc -aryl, wherein ^Rc is an alkylene chain as defined above, eg, methylene, ethylene, and the like. The alkylene chain portion of the aralkyl group is optionally substituted, as described above for the alkylene chain. The aryl portion of the aralkyl group is optionally substituted as described above for the aryl group.

"Aralkenyl" refers to a group of formula ^-Rd -aryl, wherein ^Rd is an alkenylene chain as defined above. The aryl portion of the aralkenyl group is optionally substituted as described above for the aryl group. The alkenylene chain portion of the aralkenyl is optionally substituted, as defined above for alkenylene.

"Aralkynyl" refers to a group of formula -R ^e -aryl, wherein R ^e is an alkynylene chain as defined above. The aryl portion of the aralkynyl group is optionally substituted as described above for the aryl group. The alkynylene chain portion of the aralkynyl group is optionally substituted, as defined above for the alkynylene chain.

"Aralkoxy" refers to a group bonded through an oxygen atom of the formula ^-ORc -aryl, where ^Rc is an alkylene chain as defined above, eg, methylene, ethylene, and the like group. The alkylene chain portion of the aralkyl group is optionally substituted, as described above for the alkylene chain. The aryl portion of the aralkyl group is optionally substituted as described above for the aryl group.

"Carbocyclyl" refers to stable non-aromatic monocyclic or Polycyclic hydrocarbon group. In certain embodiments, carbocyclyl groups contain three to ten carbon atoms. In other embodiments, the carbocyclyl group contains five to seven carbon atoms. The carbocyclyl is attached to the remainder of the molecule through a single bond. Carbocyclyl groups can be saturated, (ie, containing only CC single bonds) or unsaturated (ie, containing one or more double or triple bonds). Fully saturated carbocyclyl groups are also referred to as "cycloalkyl groups". Examples of monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Unsaturated carbocyclyl groups are also referred to as "cycloalkenyl groups". Examples of monocyclic cycloalkenyl groups include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclyl groups include, for example, adamantyl, norbornyl (ie, bicyclo[2.2.1]heptyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo And [2.2.1]heptyl, and the like. Unless specifically stated otherwise in this specification, the term "carbocyclyl" is meant to include a carbocyclyl group optionally substituted with one or more substituents independently selected from the group consisting of: alkyl, alkenyl, alkyne group, halogen, fluoroalkyl, oxo, thio, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, any optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclyl Alkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R ^b -OR ^a , -R ^b -OC(O)-R ^a , -R ^b -OC( O)-OR ^a , -R ^b -OC(O)-N(R ^a ) ₂ , -R ^b -N(R ^a ) ₂ , -R ^b -C(O)R ^a , -R ^b -C( O)OR ^a , -R ^b -C(O)N(R ^a ) ₂ , -R ^b -OR ^c -C(O)N(R ^a ) ₂ , -R ^b -N(R ^a )C(O )OR ^a , -R ^b -N(R ^a )C(O)R ^a , -R ^b -N(R ^a )S(O) _t R ^a (where t is 1 or 2), -R ^b -S (O) _t R ^a (where t is 1 or 2), -R ^b -S(O) _t OR ^a (where t is 1 or 2), and -R ^b -S(O) _t N(R ^a ) ₂ (wherein t is 1 or 2), wherein each ^Ra is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl ( optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (any optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl ⁾ , each R independently is a direct bond or a straight or branched alkylene or ^alkenylene chain, and R is a straight or branched alkylene or alkenylene chain, and wherein unless otherwise indicated, the above Each of the substituents in the text is unsubstituted.

"Carbocyclylalkyl" refers to a group of formula ^-Rc -carbocyclyl, wherein ^Rc is an alkylene chain as defined above. The alkylene chain and carbocyclyl are optionally substituted as defined above.

"Carbocyclylalkynyl" refers to a group of formula ^-Rc -carbocyclyl, wherein ^Rc is an alkynylene chain as defined above. Alkynylene chains and carbocyclyl groups are optionally substituted as defined above.

"Carbocyclylalkoxy" refers to a group bonded through an oxygen atom of the formula ^-ORc -carbocyclyl, wherein ^Rc is an alkylene chain as defined above. The alkylene chain and carbocyclyl are optionally substituted as defined above.

As used herein, a "carboxylic acid bioisostere" refers to a functional group or functional moiety that exhibits similar physical, biological, and/or chemical properties as a carboxylic acid moiety. Examples of carboxylic acid bioisosteres include, but are not limited to,

及类似物。

and the like.

"Halo" or "halogen" refers to a bromo, chloro, fluoro, or iodo substituent.

"Fluoroalkyl" refers to an alkyl group as defined above substituted with one or more fluoro groups as defined above, eg trifluoromethyl, difluoromethyl, fluoromethyl, 2,2 , 2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. The alkyl portion of a fluoroalkyl group can be optionally substituted as defined above for an aryl group.

"Heterocyclyl" refers to a stable three- to eighteen-membered non-aromatic ring group containing two to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. Unless specifically stated otherwise in this specification, a heterocyclyl group is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems. Heteroatoms in a heterocyclyl group can be optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. Heterocyclyl groups are partially or fully saturated. A heterocyclyl group can be attached to the remainder of the molecule through any atom of the ring. Examples of such heterocyclyl groups include, but are not limited to, dioxolane, thieno[1,3]dithiyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazole Alkyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidinyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, trithianyl, tetra Hydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless specifically stated otherwise in this specification, the term "heterocyclyl" is meant to include heterocyclyl as defined above optionally substituted with one or more substituents selected from the group consisting of: alkyl, alkenyl , alkynyl, halogen, fluoroalkyl, oxo, thio, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl , optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclyl Cycloalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R ^b -OR ^a , -R ^b -OC(O)-R ^a , -R ^b - OC(O)-OR ^a , -R ^b -OC(O)-N(R ^a ) ₂ , -R ^b -N(R ^a ) ₂ , -R ^b -C(O)R ^a , -R ^b - C(O)OR ^a , -R ^b -C(O)N(R ^a ) ₂ , -R ^b -OR ^c -C(O)N(R ^a ) ₂ , -R ^b -N(R ^a )C (O)OR ^a , -R ^b -N(R ^a )C(O)R ^a , -R ^b -N(R ^a )S(O) _t R ^a (where t is 1 or 2), -R ^b -S(O) _t R ^a (where t is 1 or 2), -R ^b -S(O) _t OR ^a (where t is 1 or 2) and -R ^b -S(O) _t N(R ^a ) ₂ (wherein t is 1 or 2 ⁾ , wherein each R is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkane group (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (any optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (any optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each R ^b is independently a direct bond or a straight or branched alkylene or ^alkenylene chain, and R is a straight or branched alkylene or alkenylene chain, and wherein unless otherwise indicated, Otherwise each of the above substituents is unsubstituted.

"N-heterocyclyl" or "N-attached heterocyclyl" refers to a group containing at least one nitrogen and wherein the point of attachment of the heterocyclyl group to the remainder of the molecule is through the heterocyclyl group in the heterocyclyl group A heterocyclyl group as defined above for a nitrogen atom. N-heterocyclyl groups are optionally substituted as described above for heterocyclyl groups. Examples of such N-heterocyclyl groups include, but are not limited to, 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazole alkyl.

"C-heterocyclyl" or "C-attached heterocyclyl" refers to containing at least one heteroatom and wherein the point of attachment of the heterocyclyl group to the remainder of the molecule is through the heterocyclyl group A heterocyclyl group as defined above for the carbon atoms in the group. The C-heterocyclyl group is optionally substituted as described above for the heterocyclyl group. Examples of such C-heterocyclyl groups include, but are not limited to, 2-morpholinyl, 2- or 3- or 4-piperidinyl, 2-piperazinyl, 2- or 3-pyrrolidinyl, and the like thing.

"Heterocyclylalkyl" refers to a group of formula ^-Rc -heterocyclyl, wherein ^Rc is an alkylene chain as defined above. If the heterocyclyl group is a nitrogen-containing heterocyclyl group, the heterocyclyl group is optionally attached to the alkyl group at a nitrogen atom. The alkylene chain of a heterocyclylalkyl group is optionally substituted, as defined above for the alkylene chain. The heterocyclyl portion of a heterocyclylalkyl group is optionally substituted, as defined above for a heterocyclyl group.

"Heterocyclylalkoxy" refers to a group bonded through an oxygen atom of the formula ^-ORc -heterocyclyl, where ^Rc is an alkylene chain as defined above. If the heterocyclyl group is a nitrogen-containing heterocyclyl group, the heterocyclyl group is optionally attached to the alkyl group at a nitrogen atom. The alkylene chain of a heterocyclylalkoxy group is optionally substituted, as defined above for the alkylene chain. The heterocyclyl portion of a heterocyclylalkoxy group is optionally substituted, as defined above for a heterocyclyl group.

"Heteroaryl" refers to a group derived from a three- to eighteen-membered aromatic ring group containing two to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen, and sulfur . As used herein, a heteroaryl group may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, ie, according to Huckel's theory, its Contains a cyclic, delocalized (4n+2)π electron system. Heteroaryl groups include fused or bridged ring systems. Heteroatoms in heteroaryl groups are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. A heteroaryl group is attached to the remainder of the molecule through any atom of the ring. Examples of heteroaryl groups include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzene oxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, Benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxin, benzopyran, benzopyrone, benzofuran, benzofuranone, benzothienyl (benzothiophenyl), benzothiophene Do[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazolyl, cinnolinyl, cyclopentadieno[ d] pyrimidinyl (cyclopenta[d]pyrimidinyl), 6,7-dihydro-5H-cyclopentadieno[4,5]thieno[2,3-d]pyrimidinyl (6,7-dihydro-5H -cyclopenta[4,5]thieno[2,3-d]pyrimidinyl), 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6 ,7-Dihydro-5H-benzo[6,7]cycloheptatrieno[1,2-c]pyridazinyl (6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2 -c]pyridazinyl), dibenzofuranyl, dibenzothienyl, furanyl, furanonyl, furo[3,2-c]pyridyl, 5,6,7,8,9,10-hexa Hydrocyclooctatetraeno[d]pyrimidinyl (5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl), 5,6,7,8,9,10-hexahydrocyclooctatetra Eno[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocyclooctatetraeno[d]pyridyl, isothiazolyl, imidazolyl, indazolyl, indolyl, Indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolinyl, indolizinyl, isoxazolyl, 5,8-methylene-5,6,7,8- Tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinyl, oxadiazolyl, 2-oxoazepine, oxazolyl, oxirane, 5,6,6a, 7,8,9,10,10a-Octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, Pteridyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d ] pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8 -Tetrahydroquine oxazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cycloheptatriene Do[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, tris azolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pyridyl, and thienyl (thiophenyl) (ie, thienyl). Unless specifically stated otherwise in this specification, the term "heteroaryl" is meant to include a heteroaryl group as defined above optionally substituted with one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl, haloalkynyl, oxo, thio, cyano, nitro, optionally substituted aryl, optionally substituted aryl alkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R ^b -OR ^a , -R ^b - OC(O)-R ^a , -R ^b -OC(O)-OR ^a , -R ^b -OC(O)-N(R ^a ) ₂ , -R ^b -N(R ^a ) ₂ , -R ^b -C(O)R ^a , -R ^b -C(O)OR ^a , -R ^b -C(O)N(R ^a ) ₂ , -R ^b -OR ^c -C(O)N(R ^a ) ₂ , -R ^b -N(R ^a )C(O)OR ^a , -R ^b -N(R ^a )C(O)R ^a , -R ^b -N(R ^a )S(O) _t R ^a (where t is 1 or 2), -R ^b -S(O) _t R ^a (where t is 1 or 2), -R ^b -S(O) _t OR ^a (where t is 1 or 2) and - R ^b —S(O) _t N(R ^a ) ₂ (wherein t is 1 or 2), wherein each R ^a is independently hydrogen, alkyl (optionally replaced by halogen, hydroxy, methoxy, or tris fluoromethyl substituted), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or substituted with trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or substituted with trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl substituted), each R is independently ^a direct bond or a straight or branched alkylene or ^alkenylene chain, and R is a straight or branched alkylene chain or alkenylene chain, and wherein each of the above substituents is unsubstituted unless otherwise indicated.

"N-heteroaryl" refers to a heteroaryl as defined above containing at least one nitrogen and wherein the point of attachment of the heteroaryl group to the remainder of the molecule is through a nitrogen atom in the heteroaryl group base group. N-heteroaryl groups are optionally substituted as described above for heteroaryl groups.

"C-heteroaryl" refers to a heteroaryl group as defined above and wherein the point of attachment of the heteroaryl group to the remainder of the molecule is through a carbon atom in the heteroaryl group. C-heteroaryl groups are optionally substituted as described above for heteroaryl groups.

"Heteroarylalkyl" refers to a group of formula ^-Rc -heteroaryl, wherein ^Rc is an alkylene chain as defined above. If the heteroaryl group is a nitrogen-containing heteroaryl group, the heteroaryl group is optionally attached to the alkyl group at the nitrogen atom. The alkylene chain of a heteroarylalkyl group is optionally substituted, as defined above for the alkylene chain. The heteroaryl portion of a heteroarylalkyl group is optionally substituted, as defined above for a heteroaryl group.

"Heteroarylalkoxy" refers to a group bonded through an oxygen atom of the formula ^-ORc -heteroaryl, where ^Rc is an alkylene chain as defined above. If the heteroaryl group is a nitrogen-containing heteroaryl group, the heteroaryl group is optionally attached to the alkyl group at the nitrogen atom. The alkylene chain of the heteroarylalkoxy group is optionally substituted, as defined above for the alkylene chain. The heteroaryl portion of a heteroarylalkoxy group is optionally substituted, as defined above for a heteroaryl group.

The compounds disclosed herein may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms. Unless otherwise stated, it is intended that all stereoisomeric forms of the compounds disclosed herein are contemplated by this disclosure. When the compounds described herein contain olefinic double bonds, and unless otherwise specified, it is intended that this disclosure includes both E and Z geometric isomers (eg, cis or trans). Likewise, all possible isomers as well as their racemic and optically pure forms, and all tautomeric forms are also intended to be included. The term "geometric isomer" refers to an E or Z geometric isomer (eg, cis or trans) of an olefinic double bond. The term "positional isomers" refers to structural isomers around a central ring, such as ortho, meta, and para isomers around a benzene ring.

"Tautomer" refers to a molecule in which migration of protons from one atom of a molecule to another atom of the same molecule is possible. The compounds provided herein may, in certain embodiments, exist as tautomers. In cases where tautomerization is possible, a chemical equilibrium of tautomers will exist. The exact ratio of tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibria include:

"Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances when said event or circumstance occurs and wherein said event or circumstance does not what happened. For example, "optionally substituted aryl" means that the aryl group may or may not be substituted and means that the description includes both substituted aryl groups and unsubstituted aryl groups.

"Pharmaceutically acceptable salts" include both acid addition salts and base addition salts. The pharmaceutically acceptable salts of any of the Substituted Heterocycle Derivative Compounds described herein are intended to encompass any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

"Pharmaceutically acceptable acid addition salts" refers to those salts that retain the biological potency and properties of the free base, are not biologically or otherwise undesirable, and are formed with the following inorganic acids: for example, hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts formed with organic acids such as aliphatic mono- and aliphatic dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, Aliphatic acids, as well as aromatic sulfonic acids, and the like, and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, lemon acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Thus, exemplary salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate , chloride, bromide, iodide, acetate, trifluoroacetate, propionate, octanoate, isobutyrate, oxalate, malonate, succinate, suberate , Sebacate, Fumarate, Maleate, Mandelate, Benzoate, Chlorobenzoate, Methylbenzoate, Dinitrobenzoate, Phthalate acid salts, benzenesulfonates, tosylates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Salts of amino acids are also contemplated, such as arginine, gluconate, and galacturonate (see, eg, Berge S.M. et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66:1-19 (1997), which is hereby incorporated by reference in its entirety). Acid addition salts of basic compounds can be prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt according to methods and techniques familiar to the skilled artisan.

"Pharmaceutically acceptable base addition salts" refers to those salts that retain the biological efficacy and properties of the free acid, which salts are not biologically or otherwise undesirable. These salts are prepared from the addition of an inorganic or organic base to the free acid. Pharmaceutically acceptable base addition salts can be formed with metals or amines such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Salts derived from organic bases include, but are not limited to, primary, secondary, and tertiary amines, substituted amines (including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins) such as isopropylamine, trimethylamine Amine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine , caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenediphenylamine, N - Salts of methylglucamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. See Berge et al., supra.

As used herein, "treatment" or "treating" or "palliating" or "ameliorating" are used interchangeably herein. These terms refer to methods for obtaining beneficial or desired results including, but not limited to, therapeutic benefit and/or prophylactic benefit. "Therapeutic benefit" means the eradication or alleviation of the underlying disorder being treated. Furthermore, therapeutic benefit is achieved by eradicating or reducing one or more of the physiological symptoms associated with the underlying disorder, such that improvement is observed in the patient, although the patient may still be afflicted by the underlying disorder. For prophylactic benefit, the composition can be administered to a patient at risk of developing a particular disease, or to a patient reporting one or more physiological symptoms of the disease, although a diagnosis of the disease may not have been made.

"Prodrug" is meant to indicate a compound that can be converted under physiological conditions or converted by solvolysis to the biologically active compound described herein. Thus, the term "prodrug" refers to a precursor of a pharmaceutically acceptable biologically active compound. A prodrug may be inactive when administered to a subject, but is converted to the active compound in vivo, eg, by hydrolysis. Prodrug compounds often offer solubility, histocompatibility or delayed release advantages in mammalian organisms (see, eg, Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 page (Elsevier, Amsterdam).

Discussion of prodrugs is in Higuchi, T. et al., "Pro-drugs as Novel Delivery Systems," A.C.S. Symposium Series, Vol. 14 and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated by reference in their entirety.

The term "prodrug" is also meant to include any covalently bonded carrier that releases the active compound in vivo when such prodrug is administered to a mammalian subject. Prodrugs of an active compound as described herein can be prepared by modifying functional groups present in the active compound in a manner such that the modification is cleaved to the parent active compound in routine manipulation or in vivo. Prodrugs include compounds in which a hydroxyl, amino, or sulfhydryl group is bonded to any group that, when the prodrug of the active compound is administered to a mammalian subject, is cleaved to form a free hydroxyl, free amino group or free thiol group. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives and the like of alcohol functional or amine functional groups in the active compound.

Substituted Heterocyclic Derivative Compounds

Described herein are substituted heterocyclic derivative compounds that are lysine-specific demethylase-1 inhibitors. These compounds and compositions comprising these compounds are useful for the treatment of cancer and neoplastic diseases. The compounds described herein are useful for the treatment of prostate, breast, bladder, lung and/or melanoma and similar cancers.

One embodiment provides a compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof,

in,

X and Y are each independently selected from CH, CF, C _- CH or N;

Z is selected from C-H or N;

R is selected from hydrogen, halogen, aryl, heteroaryl, heterocyclyl, carbocyclyl, alkoxy, cycloalkylalkoxy or aralkoxy;

W is -L-G, heterocyclyl or heteroaryl;

L is an alkylene group;

G is -N(R ¹ ) ₂ , heterocyclyl or heteroaryl; and

R ¹ is hydrogen or alkyl.

Another embodiment provides a compound having the structure of formula (I), or a pharmaceutically acceptable salt thereof, wherein R is selected from aryl, heteroaryl, heterocyclyl, carbocyclyl, alkoxy, cycloalkane alkoxy or aralkoxy.

Another embodiment provides a compound having the structure of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CH. Another embodiment provides a compound having the structure of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is N. Another embodiment provides a compound having the structure of formula (I), or a pharmaceutically acceptable salt thereof, wherein X is CH. Another embodiment provides a compound having the structure of Formula (I), or a pharmaceutically acceptable salt thereof, wherein X is CF. Another embodiment provides a compound having the structure of Formula (I), or a pharmaceutically acceptable salt thereof, wherein X is C- _CH3 . Another embodiment provides a compound having the structure of Formula (I), or a pharmaceutically acceptable salt thereof, wherein X is N. Another embodiment provides a compound having the structure of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Y is CH. Another embodiment provides a compound having the structure of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Y is CF. Another embodiment provides a compound having the structure of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Y is C- _CH3 . Another embodiment provides a compound having the structure of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Y is N. Another embodiment provides a compound having the structure of Formula (I), or a pharmaceutically acceptable salt thereof, wherein X is CH and Y is CH. Another embodiment provides a compound having the structure of Formula (I), or a pharmaceutically acceptable salt thereof, wherein X is CH, Y is CH, and Z is CH. Another embodiment provides a compound having the structure of Formula (I), wherein X is CH, Y is CH, and Z is N, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound having the structure of Formula (I), or a pharmaceutically acceptable salt thereof, wherein X is CH, Y is C- _CH3 , and Z is CH. Another embodiment provides a compound having the structure of Formula (I), or a pharmaceutically acceptable salt thereof, wherein X is CH, Y is C- _CH3 , and Z is N.

Another embodiment provides a compound having the structure of Formula (I), or a pharmaceutically acceptable salt thereof, wherein W is L-G. Another embodiment provides a compound having the structure of Formula (I), or a pharmaceutically acceptable salt thereof, wherein W is heterocyclyl.

Another embodiment provides a compound having the structure of Formula (I), or a pharmaceutically acceptable salt thereof, wherein W is heteroaryl. Another embodiment provides a compound having the structure of formula (I), or a pharmaceutically acceptable salt thereof, wherein W is LG, and L is selected from C ₁ alkylene, C ₁ -C ₂ alkylene, C ₁ - _C4 alkylene or C2 _{- C5} alkylene. Another embodiment provides a compound having the structure of Formula (I), or a pharmaceutically acceptable salt thereof, wherein W is LG, and L is _C1 alkylene. Another embodiment provides a compound having the structure of Formula (I), or a pharmaceutically acceptable salt thereof, wherein W is LG and G is heterocyclyl. Another embodiment provides a compound having the structure of Formula (I), or a pharmaceutically acceptable salt thereof, wherein W is LG and G is heteroaryl. Another embodiment provides a compound having the structure of Formula (I), or a pharmaceutically acceptable salt thereof, wherein W is LG and G is -N(R ¹ ) ₂ . Another embodiment provides a compound having the structure of formula (I), or a pharmaceutically acceptable salt thereof, wherein W is LG and L is selected from C ₁ alkylene, C ₁ -C ₂ alkylene, C ₁ -C ₄ alkylene or C ₂ -C ₅ alkylene, and G is -N(R ¹ ) ₂ . Another embodiment provides a compound having the structure of Formula (I), or a pharmaceutically acceptable salt thereof, wherein W is LG and G is _-NH2 . Another embodiment provides a compound having the structure of Formula (I), or a pharmaceutically acceptable salt thereof, wherein W is LG and G is -NH(alkyl). Another embodiment provides a compound having the structure of Formula (I), or a pharmaceutically acceptable salt thereof, wherein W is LG and G is -N(alkyl) ₂ .

Another embodiment provides a compound having the structure of Formula (I), or a pharmaceutically acceptable salt thereof, wherein W is L-G, G is heterocyclyl, and heterocyclyl is a nitrogen-containing heterocyclyl. Another embodiment provides a compound having the structure of formula (I), or a pharmaceutically acceptable salt thereof, wherein W is L-G, G is a heterocyclyl, the heterocyclyl is a nitrogen-containing heterocyclyl, and the containing The nitrogen heterocyclyl group is a five-membered heterocyclyl group or a six-membered heterocyclyl group. Another embodiment provides a compound having the structure of formula (I), or a pharmaceutically acceptable salt thereof, wherein W is L-G, G is a heterocyclyl group, and the heterocyclyl group is selected from:

Another embodiment provides a compound having the structure of Formula (I), or a pharmaceutically acceptable salt thereof, wherein W is a heterocyclyl group, and the heterocyclyl group is a nitrogen-containing heterocyclyl group. Another embodiment provides a compound having the structure of Formula (I), or a pharmaceutically acceptable salt thereof, wherein W is heterocyclyl, the heterocyclyl is a nitrogen-containing heterocyclyl, and the nitrogen-containing heterocyclyl is a five-membered heterocyclic group or a six-membered heterocyclic group. Another embodiment provides a compound having the structure of formula (I), or a pharmaceutically acceptable salt thereof, wherein W is a heterocyclyl group, and the heterocyclyl group is a nitrogen-containing heterocyclyl group selected from:

Another embodiment provides a compound having the structure of formula (I), or a pharmaceutically acceptable salt thereof, wherein G is a nitrogen-containing heterocyclyl group, and the heterocyclyl group is selected from:

Another embodiment provides a compound having the structure of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R is an aryl group or a heterocyclyl group. Another embodiment provides a compound having the structure of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R is an aryl group. Another embodiment provides a compound having the structure of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the aryl group is an optionally substituted phenyl group. Another embodiment provides a compound having the structure of formula (I), or a pharmaceutically acceptable salt thereof, wherein the optionally substituted phenyl group is selected from 4-methylphenyl, 4-chlorophenyl , 4-fluorophenyl, 4-cyanophenyl, 4-(methylsulfonyl)phenyl or 4-trifluoromethylphenyl.

One embodiment provides a compound having the structure of formula (II), or a pharmaceutically acceptable salt thereof,

in,

X and Y are each independently selected from CH, CF, C _- CH or N;

W is selected from CH, CF, C-Cl, C- _CH3 , C- _CF3 , C- _OCH3 , C _{- OCH2CH3} , or N;

Z is selected from -G, -CH ₂ -G, -CH ₂ -CH ₂ -G, -N(R ¹ )-G, -N(R ¹ )-CH ₂ -G, -OG, -O-CH ₂ -G or -C(O)N(R ² )(R ³ );

G is carbocyclyl, aryl, heterocyclyl or heteroaryl;

R ¹ is hydrogen or alkyl;

R2 and ^R3 are independently selected from ^hydrogen , alkyl, heterocyclyl, heterocyclylalkyl, or optionally, R2 and ^R3 are linked to form an N ^- linked heterocyclyl ring system;

R is selected from aryl, halogen, heteroaryl, heterocyclyl, carbocyclyl, alkoxy, cycloalkylalkoxy or aralkoxy.

Another embodiment provides a compound having the structure of Formula (II), or a pharmaceutically acceptable salt thereof, wherein X is CH. Another embodiment provides a compound having the structure of Formula (II), or a pharmaceutically acceptable salt thereof, wherein X is CF. Another embodiment provides a compound having the structure of Formula (II), or a pharmaceutically acceptable salt thereof, wherein X is C- _CH3 . Another embodiment provides a compound having the structure of Formula (II), or a pharmaceutically acceptable salt thereof, wherein X is N. Another embodiment provides a compound having the structure of Formula (II), or a pharmaceutically acceptable salt thereof, wherein Y is CH. Another embodiment provides a compound having the structure of Formula (II), or a pharmaceutically acceptable salt thereof, wherein Y is CF. Another embodiment provides a compound having the structure of Formula (II), or a pharmaceutically acceptable salt thereof, wherein Y is C- _CH3 . Another embodiment provides a compound having the structure of Formula (II), or a pharmaceutically acceptable salt thereof, wherein Y is N. Another embodiment provides a compound having the structure of Formula (II), or a pharmaceutically acceptable salt thereof, wherein X is CH and Y is CH. Another embodiment provides a compound having the structure of Formula (II), or a pharmaceutically acceptable salt thereof, wherein W is N. Another embodiment provides a compound having the structure of Formula (II), or a pharmaceutically acceptable salt thereof, wherein W is CH. Another embodiment provides a compound having the structure of Formula (II), or a pharmaceutically acceptable salt thereof, wherein X is CH and W is N. Another embodiment provides a compound having the structure of Formula (II), or a pharmaceutically acceptable salt thereof, wherein X is CH and W is CH. Another embodiment provides a compound having the structure of Formula (II), wherein X is CH, Y is CH, and W is N, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound having the structure of Formula (II), or a pharmaceutically acceptable salt thereof, wherein X is CH, Y is CH, and W is CH.

Another embodiment provides a compound having the structure of Formula (II), or a pharmaceutically acceptable salt thereof, wherein Z is -O- _CH2 -G. Another embodiment provides a compound having the structure of Formula (II), or a pharmaceutically acceptable salt thereof, wherein Z is -OG. Another embodiment provides a compound having the structure of Formula (II), or a pharmaceutically acceptable salt thereof, wherein Z is -N(R ¹ )-CH ₂ -G.

Another embodiment provides a compound having the structure of Formula (II), or a pharmaceutically acceptable salt thereof, wherein Z is -N(R ¹ )-G. Another embodiment provides a compound having the structure of Formula (II), or a pharmaceutically acceptable salt thereof, wherein Z is _-CH2 - _CH2 -G.

Another embodiment provides a compound having the structure of Formula (II), or a pharmaceutically acceptable salt thereof, wherein Z is _-CH2 -G. Another embodiment provides a compound having the structure of Formula (II), or a pharmaceutically acceptable salt thereof, wherein Z is -G.

Another embodiment provides a compound having the structure of Formula (II), or a pharmaceutically acceptable salt thereof, wherein Z is -C(O)N(R ² )(R ³ ). Another embodiment provides a compound having the structure of Formula (II), or a pharmaceutically acceptable salt thereof, wherein Z is -C(O)N(R ² )(R ³ ), and R ² and R ³ are independently is selected from hydrogen or alkyl. Another embodiment provides a compound having the structure of Formula (II), or a pharmaceutically acceptable salt thereof, wherein Z is -C(O)N(R ² )(R ³ ), and R ² and R ³ are independently is selected from hydrogen, alkyl or heterocyclyl.

Another embodiment provides a compound having the structure of Formula (II), or a pharmaceutically acceptable salt thereof, wherein Z is -C(O)N(R ² )(R ³ ), and R ² and R ³ are independently is selected from hydrogen, alkyl or heterocyclylalkyl.

Another embodiment provides a compound having the structure of Formula (II), or a pharmaceutically acceptable salt thereof, wherein Z is ^-C (O)N(R2)( ^R3 ), ^both R2 and ^R3 are ^both alkyl, and R2 and ^R3 are linked to form an N-linked heterocyclyl ring system. Another embodiment provides a compound having the structure of Formula (II), or a pharmaceutically acceptable salt thereof, wherein Z is ^-C (O)N(R2)( ^R3 ), ^both R2 and ^R3 are ^both alkyl, R2 and ^R3 are linked to form an N-linked heterocyclyl group, and the heterocyclyl group is selected from optionally substituted piperidinyl groups, piperazinyl groups, morpholinyl groups or a pyrrolidinyl group.

Another embodiment provides a compound having the structure of Formula (II), or ^a pharmaceutically acceptable salt thereof, wherein Z is -N(R1) _-CH2 ^- G, and R1 is hydrogen. Another embodiment provides a compound having the structure of Formula (II), or a pharmaceutically acceptable salt thereof, wherein Z is -N(R ¹ )-G, and R ¹ is hydrogen.

Another embodiment provides a compound having the structure of Formula (II), or a pharmaceutically acceptable salt thereof, wherein Z is -N(R ¹ )-CH ₂ -G, and R ¹ is alkyl. Another embodiment provides a compound having the structure of Formula (II), or a pharmaceutically acceptable salt thereof, wherein Z is -N(R ¹ )-CH ₂ -G, R ¹ is alkyl, and alkyl is C ₁ -C ₄ alkyl. Another embodiment provides a compound having the structure of Formula (II), or a pharmaceutically acceptable salt thereof, wherein Z is -N(R ¹ )-G, and R ¹ is alkyl. Another embodiment provides a compound having the structure of Formula (II), or a pharmaceutically acceptable salt thereof, wherein Z is -N(R ¹ )-G, R ¹ is alkyl, and alkyl is C ₁ - C ₄ alkyl.

Another embodiment provides a compound having the structure of Formula (II), or a pharmaceutically acceptable salt thereof, wherein G is heterocyclyl. Another embodiment provides a compound having the structure of Formula (II), or a pharmaceutically acceptable salt thereof, wherein G is a nitrogen-containing heterocyclyl group. Another embodiment provides a compound having the structure of Formula (II), or a pharmaceutically acceptable salt thereof, wherein G is a nitrogen-containing heterocyclyl, and the nitrogen-containing heterocyclyl is a five-membered or six-membered heterocyclyl Heterocyclyl. Another embodiment provides a compound having the structure of Formula (II), or a pharmaceutically acceptable salt thereof, wherein G is a heterocyclyl group, and the heterocyclyl group is selected from:

Another embodiment provides a compound having the structure of formula (II), or a pharmaceutically acceptable salt thereof, wherein G is a nitrogen-containing heterocyclyl group, and the heterocyclyl group is selected from:

Another embodiment provides a compound having the structure of Formula (II), or a pharmaceutically acceptable salt thereof, wherein G is a heterocyclyl group, and the heterocyclyl group is selected from optionally substituted piperidinyl groups , a piperazinyl group, a morpholinyl group or a pyrrolidinyl group.

Another embodiment provides a compound having the structure of Formula (II), or a pharmaceutically acceptable salt thereof, wherein R is selected from the group consisting of aryl, heteroaryl, heterocyclyl, carbocyclyl, alkoxy, cycloalkane alkoxy or aralkoxy. Another embodiment provides a compound having the structure of Formula (II), or a pharmaceutically acceptable salt thereof, wherein R is aryl. Another embodiment provides a compound having the structure of Formula (II), or a pharmaceutically acceptable salt thereof, wherein R is an aryl group, and the aryl group is an optionally substituted phenyl group. Another embodiment provides a compound having the structure of Formula (II), or a pharmaceutically acceptable salt thereof, wherein R is an aryl group, the aryl group is an optionally substituted phenyl group, and optionally The substituted phenyl group is selected from 4-methylphenyl, 4-chlorophenyl, 4-fluorophenyl, 4-cyanophenyl, 4-(methylsulfonyl)phenyl or 4-trifluoromethyl base phenyl.

One embodiment provides a compound having the structure of formula (III), or a pharmaceutically acceptable salt thereof,

in,

X and Y are each independently selected from CH, CF, C _- CH or N;

Z is selected from -G, -CH ₂ -G, -CH ₂ -CH ₂ -G, -N(R ¹ )-G, -N(R ¹ )-CH ₂ -G, -OG, -O-CH ₂ -G or -C(O)N(R ² )(R ³ );

G is carbocyclyl, aryl, heterocyclyl or heteroaryl;

R ¹ is hydrogen or alkyl;

R2 and ^R3 are independently selected from ^hydrogen , alkyl, heterocyclyl, heterocyclylalkyl, or optionally, R2 and ^R3 are linked to form an N ^- linked heterocyclyl ring system;

R is selected from alkoxy, carbocyclylalkoxy, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, alkynyl or carbocyclylalkynyl.

Another embodiment provides a compound having the structure of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH. Another embodiment provides a compound having the structure of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CF. Another embodiment provides a compound having the structure of formula (III), or a pharmaceutically acceptable salt thereof, wherein X is C- _CH3 . Another embodiment provides a compound having the structure of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is N. Another embodiment provides a compound having the structure of Formula (III), or a pharmaceutically acceptable salt thereof, wherein Y is CH. Another embodiment provides a compound having the structure of Formula (III), or a pharmaceutically acceptable salt thereof, wherein Y is CF. Another embodiment provides a compound having the structure of Formula (III), or a pharmaceutically acceptable salt thereof, wherein Y is C- _CH3 . Another embodiment provides a compound having the structure of Formula (III), or a pharmaceutically acceptable salt thereof, wherein Y is N. Another embodiment provides a compound having the structure of Formula (III), or a pharmaceutically acceptable salt thereof, wherein X is CH and Y is CH.

Another embodiment provides a compound having the structure of Formula (III), or a pharmaceutically acceptable salt thereof, wherein Z is -O- _CH2 -G.

Another embodiment provides a compound having the structure of Formula (III), or a pharmaceutically acceptable salt thereof, wherein Z is -O-G.

Another embodiment provides a compound having the structure of Formula (III), or a pharmaceutically acceptable salt thereof, wherein Z is -N(R1) _-CH2 ^- G. Another embodiment provides a compound having the structure of Formula (III), or a pharmaceutically acceptable salt thereof, wherein Z is -N(R ¹ )-CH ₂ -G, and R ¹ is hydrogen. Another embodiment provides a compound having the structure of Formula (III), or a pharmaceutically acceptable salt thereof, wherein Z is -N(R ¹ )-CH ₂ -G, and R ¹ is alkyl.

Another embodiment provides a compound having the structure of Formula (III), or a pharmaceutically acceptable salt thereof, wherein Z is -N(R ¹ )-G. Another embodiment provides a compound having the structure of Formula (III), or a pharmaceutically acceptable salt thereof, wherein Z is -N(R ¹ )-G, and R ¹ is hydrogen. Another embodiment provides a compound having the structure of Formula (III), or a pharmaceutically acceptable salt thereof, wherein Z is -N(R ¹ )-G, and R ¹ is alkyl.

Another embodiment provides a compound having the structure of Formula (III), or a pharmaceutically acceptable salt thereof, wherein Z is _-CH2 - _CH2 -G. Another embodiment provides a compound having the structure of Formula (III), or a pharmaceutically acceptable salt thereof, wherein Z is _-CH2 -G. Another embodiment provides a compound having the structure of Formula (III), or a pharmaceutically acceptable salt thereof, wherein Z is -G. Another embodiment provides a compound having the structure of Formula (III), or a pharmaceutically acceptable salt thereof, wherein Z is -C(O)N(R ² )(R ³ ).

Another embodiment provides a compound having the structure of Formula (III), or a pharmaceutically acceptable salt thereof, wherein Z is -C(O)N(R ² )(R ³ ), and R ² and R ³ are independently is selected from hydrogen or alkyl. Another embodiment provides a compound having the structure of Formula (III), or a pharmaceutically acceptable salt thereof, wherein Z is -C(O)N(R ² )(R ³ ), and R ² and R ³ are independently is selected from hydrogen, alkyl or heterocyclyl. Another embodiment provides a compound having the structure of Formula (III), or a pharmaceutically acceptable salt thereof, wherein Z is -C(O)N(R ² )(R ³ ), and R ² and R ³ are independently is selected from hydrogen, alkyl or heterocyclylalkyl. Another embodiment provides a compound having the structure of Formula (III), or a pharmaceutically acceptable salt thereof, wherein Z is -C(O)N(R ² )(R ³ ), and R ² and R ³ are linked to form N-linked heterocyclyl ring systems. Another embodiment provides a compound having the structure of formula (III), or a pharmaceutically acceptable salt thereof, wherein Z is -C(O)N(R ² )(R ³ ), and R ² and R ³ are linked to An N-linked heterocyclyl ring system is formed, and the heterocyclyl group is selected from an optionally substituted piperidinyl group, a piperazinyl group, a morpholinyl group, or a pyrrolidinyl group. Another embodiment provides a compound having the structure of Formula (III), or a pharmaceutically acceptable salt thereof, wherein Z is ^-C (O)N(R2)( ^R3 ), ^both R2 and ^R3 are ^both alkyl, and R2 and ^R3 are linked to form an N-linked heterocyclyl ring system.

Another embodiment provides a compound having the structure of Formula (III), or a pharmaceutically acceptable salt thereof, wherein G is heterocyclyl. Another embodiment provides a compound having the structure of Formula (III), or a pharmaceutically acceptable salt thereof, wherein G is a nitrogen-containing heterocyclyl group. Another embodiment provides a compound having the structure of formula (III), or a pharmaceutically acceptable salt thereof, wherein G is a nitrogen-containing heterocyclyl, and the nitrogen-containing heterocyclyl is a five-membered or six-membered heterocyclyl Heterocyclyl. Another embodiment provides a compound having the structure of formula (III), or a pharmaceutically acceptable salt thereof, wherein G is a nitrogen-containing heterocyclyl group, and the heterocyclyl group is selected from:

Another embodiment provides a compound having the structure of formula (III), or a pharmaceutically acceptable salt thereof, wherein G is a nitrogen-containing heterocyclyl group, and the heterocyclyl group is selected from:

Another embodiment provides a compound having the structure of formula (III), or a pharmaceutically acceptable salt thereof, wherein G is heterocyclyl, and heterocyclyl is selected from optionally substituted piperidinyl groups, A piperazinyl group, a morpholinyl group or a pyrrolidinyl group.

Another embodiment provides a compound having the structure of Formula (III), or a pharmaceutically acceptable salt thereof, wherein R is selected from alkynyl or carbocyclylalkynyl. Another embodiment provides a compound having the structure of Formula (III), or a pharmaceutically acceptable salt thereof, wherein R is selected from alkoxy or carbocyclylalkoxy. Another embodiment provides a compound having the structure of Formula (III), or a pharmaceutically acceptable salt thereof, wherein R is selected from heteroaryl or heterocyclyl. Another embodiment provides a compound having the structure of formula (III), or a pharmaceutically acceptable salt thereof, wherein R is selected from carbocyclyl, carbocyclylalkyl, aryl, or aralkyl.

Another embodiment provides a compound having the structure of Formula (III), or a pharmaceutically acceptable salt thereof, wherein R is aryl. Another embodiment provides a compound having the structure of Formula (III), or a pharmaceutically acceptable salt thereof, wherein R is an aryl group, and the aryl group is an optionally substituted phenyl group. Another embodiment provides a compound having the structure of formula (III), or a pharmaceutically acceptable salt thereof, wherein R is an aryl group, and the aryl group is an optionally substituted phenyl group, said The optionally substituted phenyl group is selected from 4-methylphenyl, 4-chlorophenyl, 4-fluorophenyl, 4-cyanophenyl, 4-(methylsulfonyl)phenyl or 4- Trifluoromethylphenyl.

One embodiment provides a compound having the structure of formula (IV) or a pharmaceutically acceptable salt thereof,

in,

X and Y are each independently selected from CH, CF, C _- CH or N;

Z is selected from -G, -CH ₂ -G, -CH ₂ -CH ₂ -G, -N(R ¹ )-G, -N(R ¹ )-CH ₂ -G, -OG, -O-CH ₂ -G or -C(O)N(R ² )(R ³ );

X ¹ , X ² and X ³ are each independently selected from N or CR ⁴ ; provided that at least one of X ¹ , X ² or X ³ is N;

G is carbocyclyl, aryl, heterocyclyl or heteroaryl;

R ¹ is hydrogen or alkyl;

R2 and ^R3 are independently selected from ^hydrogen , alkyl, heterocyclyl, heterocyclylalkyl, or optionally, R2 and ^R3 are linked to form an N ^- linked heterocyclyl ring system;

R ⁴ is hydrogen, halogen, C ₁ -C ₃ alkyl or C ₁ -C ₃ alkoxy; and

R is aryl, heteroaryl, alkynyl or cycloalkylalkynylene.

Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt thereof, wherein R is aryl or heteroaryl.

Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt thereof, wherein formula (IV) is represented by formula (IVa):

Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt thereof, wherein formula (IV) is represented by formula (IVb):

Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt thereof, wherein formula (IV) is represented by formula (IVc):

Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt thereof, wherein formula (IV) is represented by formula (IVd):

Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt thereof, wherein formula (IV) is represented by formula (IVe):

Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt thereof, wherein formula (IV) is represented by formula (IVf):

Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt thereof, wherein formula (IV) is represented by formula (IVg):

Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt thereof, wherein X is CH. Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt thereof, wherein X is CF. Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt thereof, wherein X is C- _CH3 . Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt thereof, wherein X is N. Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt thereof, wherein Y is CH. Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt thereof, wherein Y is CF. Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt thereof, wherein Y is C- _CH3 . Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt thereof, wherein Y is N. Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt thereof, wherein X is CH and Y is CH.

Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt thereof, wherein Z is -O- _CH2 -G. Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt thereof, wherein Z is -OG. Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt thereof, wherein Z is -N(R1) _-CH2 ^- G. Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt thereof, wherein Z is -N(R ¹ )-G. Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt thereof, wherein Z is _-CH2 - _CH2 -G. Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt thereof, wherein Z is _-CH2 -G. Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt thereof, wherein Z is -G. Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt thereof, wherein Z is -C(O)N(R ² )(R ³ ). Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt thereof, wherein Z is -C(O)N(R ² )(R ³ ), and R ² and R ³ are independently selected from hydrogen or alkyl. Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt thereof, wherein Z is -C(O)N(R ² )(R ³ ), and R ² and R ³ are independently selected from Heterocyclyl or heterocyclylalkyl. Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt thereof, wherein Z is -C(O)N(R ² )(R ³ ), and R ² and R ³ are linked to form N - a linked heterocyclyl ring system.

Another embodiment provides a compound of formula (IV), or ^a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen. Another embodiment provides a compound of formula (IV), or ^a pharmaceutically acceptable salt thereof, wherein R1 is alkyl.

Another embodiment provides a compound of formula ( ^IV ), or a pharmaceutically acceptable salt thereof, wherein R4 is hydrogen. Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt thereof, wherein R ⁴ is C ₁ -C ₃ alkoxy.

Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt thereof, wherein G is heterocyclyl. Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt thereof, wherein G is a nitrogen-containing heterocyclyl group. Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt thereof, wherein G is a nitrogen-containing heterocyclyl, and the nitrogen-containing heterocyclyl is a five-membered or six-membered heterocyclyl . Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt thereof, wherein G is heterocyclyl, and the heterocyclyl is selected from:

Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt thereof, wherein G is

Another embodiment provides a compound having the structure of formula (IV), or a pharmaceutically acceptable salt thereof, wherein G is a nitrogen-containing heterocyclyl group, and the heterocyclyl group is selected from:

Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt thereof, wherein R is heteroaryl. Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt thereof, wherein R is a monocyclic nitrogen-containing heteroaryl.

Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt thereof, wherein R is a bicyclic nitrogen-containing heteroaryl. Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt thereof, wherein R is selected from:

Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt thereof, wherein R is selected from:

Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt thereof, wherein R is selected from:

Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt thereof, wherein R is aryl. Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt thereof, wherein R is an optionally substituted phenyl group. Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt thereof, wherein R is an optionally substituted phenyl group selected from 4-methylphenyl, 4-chloro phenyl, 4-fluorophenyl, 4-cyanophenyl, 4-(methylsulfonyl)phenyl or 4-trifluoromethylphenyl. Another embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt thereof, wherein R is an optionally substituted phenyl group selected from 4-methoxyphenyl, 3- Fluoro-4-methoxyphenyl or 3-chloro-4-methoxyphenyl.

Another embodiment provides a compound of formula (IVc) or a pharmaceutically acceptable salt thereof selected from the group consisting of:

4-[6-(4-Aminopiperidin-1-yl)-3-(2-methyl-2H-indazol-5-yl)pyrazin-2-yl]-2-fluorobenzonitrile,

2-Fluoro-4-[3-(2-methyl-2H-indazol-5-yl)-6-[4-(methylamino)piperidin-1-yl]pyrazin-2-yl]benzene formonitrile,

4-[6-(4-Aminopiperidin-1-yl)-3-(1-methyl-1H-indazol-5-yl)pyrazin-2-yl]-2-fluorobenzonitrile,

4-[6-(4-Aminopiperidin-1-yl)-3-(2-methyl-2H-indazol-6-yl)pyrazin-2-yl]-2-fluorobenzonitrile,

4-[6-(4-Aminopiperidin-1-yl)-3-(1-methyl-1H-1,2,3-benzotriazol-5-yl)pyrazin-2-yl]- 2-Fluorobenzonitrile,

4-[6-(4-Aminopiperidin-1-yl)-3-{3-methyl-3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl} Pyrazin-2-yl]-2-fluorobenzonitrile,

4-[6-(4-Aminopiperidin-1-yl)-3-{1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl}pyrazin-2-yl]- 2-Fluorobenzonitrile,

2-Fluoro-4-{6-[4-(methylamino)piperidinyl]-3-(1-methylbenzotriazol-5-yl)pyrazin-2-yl}benzonitrile,

4-{3-[6-(Dimethylamino)(3-pyridyl)]-6-[4-(methylamino)piperidinyl]pyrazin-2-yl}-2-fluorobenzonitrile ,

4-{3-[2-(dimethylamino)pyrimidin-5-yl]-6-[4-(methylamino)piperidinyl]pyrazin-2-yl}-2-fluorobenzonitrile,

2-Fluoro-4-{6-[4-(methylamino)piperidinyl]-3-(1-methylpyrazolo[5,4-b]pyridin-5-yl)pyrazine-2- base}benzonitrile,

4-{6-[4-(Dimethylamino)piperidinyl]-3-(2-methyl(2H-indazol-5-yl))pyrazin-2-yl}-2-fluorobenzyl Nitrile,

2-Fluoro-4-[3-(6-Fluoro-1-methylbenzimidazol-5-yl)-6-[4-(methylamino)piperidin-1-yl]pyrazin-2-yl ] benzonitrile,

4-[3-(6,7-Difluoro-1-methylbenzimidazol-5-yl)-6-[4-(methylamino)piperidin-1-yl]pyrazin-2-yl] -2-Fluorobenzonitrile,

2-Fluoro-4-[6-[4-(methylamino)piperidin-1-yl]-3-(1-propan-2-ylbenzimidazol-5-yl)pyrazin-2-yl] benzonitrile,

2-Fluoro-4-[3-[2-(1-hydroxycyclopentyl)ethynyl]-6-[4-(methylamino)piperidin-1-yl]pyrazin-2-yl]benzyl Nitrile,

2-Fluoro-4-[6-[4-(methylamino)piperidin-1-yl]-3-(1-methylbenzimidazol-5-yl)pyrazin-2-yl]benzonitrile ,

2-Fluoro-4-[3-(3-hydroxy-3-methylbut-1-ynyl)-6-[4-(methylamino)piperidin-1-yl]pyrazin-2-yl] benzonitrile,

2-Fluoro-4-[3-(6-Fluoro-1-propan-2-ylbenzimidazol-5-yl)-6-[4-(methylamino)piperidin-1-yl]pyrazine- 2-yl]benzonitrile,

2-Fluoro-4-[6-[4-(methylamino)piperidin-1-yl]-3-(1-propan-2-ylbenzimidazol-5-yl)pyrazin-2-yl] benzonitrile,

4-[3-(1-Ethyl-6-fluorobenzimidazol-5-yl)-6-[4-(methylamino)piperidin-1-yl]pyrazin-2-yl]-2- Fluorobenzonitrile,

4-[6-(4-Aminopiperidin-1-yl)-3-(6-fluoro-1-propan-2-ylbenzimidazol-5-yl)pyrazin-2-yl]-2-fluoro benzonitrile,

4-[6-(4-Aminopiperidin-1-yl)-3-(1-ethyl-6-fluorobenzimidazol-5-yl)pyrazin-2-yl]-2-fluorobenzonitrile ,

4-[6-(4-Aminopiperidin-1-yl)-3-(1-prop-2-ylbenzimidazol-5-yl)pyrazin-2-yl]-2-fluorobenzonitrile,

4-[6-(4-Aminopiperidin-1-yl)-3-(6,7-difluoro-1-propan-2-ylbenzimidazol-5-yl)pyrazin-2-yl]- 2-Fluorobenzonitrile,

4-[6-(4-Aminopiperidin-1-yl)-3-(1-ethyl-6,7-difluorobenzimidazol-5-yl)pyrazin-2-yl]-2-fluoro benzonitrile, or

4-[6-(4-Aminopiperidin-1-yl)-3-(6,7-difluoro-1-methylbenzimidazol-5-yl)pyrazin-2-yl]-2-fluoro benzonitrile.

In certain embodiments, the Substituted Heterocycle Derivative Compounds described herein have the structures provided in Table 1.

Table 1

In certain embodiments, the Substituted Heterocycle Derivative Compounds described herein have the structures provided in Table 2.

Table 2

Preparation of Substituted Heterocyclic Derivative Compounds

The compounds used in the reactions described herein are prepared according to organic synthesis techniques known to those skilled in the art starting from commercially available chemicals and/or compounds described in the chemical literature. "Commercially available chemicals" were obtained from standard commercial sources including Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, U.K.), BDH Inc. (Toronto, Canada), Bionet (Cornwall, U.K.), Chemservice Inc. (West Chester, PA), Crescent Chemical Co. (Hauppauge, NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY) NY), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, UK), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co. Ltd. (Cornwall, UK), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CN), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD) and Wako Chemicals USA, Inc. (Richmond, VA).

Methods known to those of ordinary skill in the art are identified through various reference books and databases. Suitable references and monographs detailing the synthesis of reactants useful in the preparation of the compounds described herein or providing references to papers describing the preparations include, for example, "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; S.R. Sandler et al., "Organic Functional Group Preparations," 2nd Edition, Academic Press, New York, 1983; H.O House, "Modern Synthetic Reactions," 2nd Edition, W.A. Banjamin, Inc. Menlo Park, Calif. 1972; T.L. Kirchrist, "Heterocyclic Chemistry", 2nd edition, John Wiley & Sons, New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th edition, Wiley Interscience, New York, 1992. Additional suitable references and monographs detailing the synthesis of reactants useful in the preparation of the compounds described herein or providing references to papers describing the preparations include, for example, Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods" , Starting Materials", Second Revised Supplement (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, R.V. "Organic Chemistry, An IntermediateText" (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, R.C. "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure" pp. 4th edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J. (ed.) "Modern Carbonyl Chemistry" (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S . "Patai's 1992 Guide to the Chemistry of Functional Groups" (1992) Interscience ISBN: 0-471-93022-9; Solomons, T.W.G. "Organic Chemistry" 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J.C., "Intermediate Organic Chemistry" 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2; "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia" (1999) John Wiley & Sons, ISBN: 3-527-29645-X , in 8 volumes; "Organic Reactions" (1942-2000) John Wiley & Sons, in over 55 volumes; and "Chemistry of Functional Groups" John Wiley & Sons, in 73 volumes.

Specific and similar reactants can also be indexed by known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, available in most public and university libraries and identified through online databases (American Chemical Society, Washington, D.C., can be contacted for more details). Chemicals that are known in the catalog but not commercially available can be prepared by custom chemical synthesis facilities, many of which are standard chemical suppliers (eg, those listed above) offering custom synthesis services. A reference for the preparation and selection of pharmaceutically acceptable salts of the Substituted Heterocyclic Derivative Compounds described herein is P.H. Sstahl & C.G. Wermuth "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002.

Substituted Heterocycle Derivative Compounds are prepared by the general synthetic routes described below in Schemes 1-6.

plan 1

Referring to Scheme 1, Compound A is protected by the use of a phenylsulfonyl group. Compound B is oxidized and chlorinated to yield Compound D. For example, chlorination can occur by formation of pyridine N-oxide compound C followed by treatment with a suitable chlorinating agent such as _POCl3 . Compound D is converted to compound F via a palladium-mediated cross-coupling reaction with a suitable coupling partner such as boronic acid EB(OH) ₂ . Compound F is selectively deprotected to form compound G under basic conditions. The alkylation of compound G is carried out under basic conditions with an alkyl halide to form compound K. Compound K is subjected to a palladium-mediated cross-coupling reaction with a suitable coupling partner such as boronic acid LB(OH) ₂ to give compound M.

Scenario 2

Referring to Scheme 2, compound F is converted to compound Q via a palladium-mediated cross-coupling reaction with a suitable coupling partner such as boronic acid PB(OH) ₂ . Compound Q is deprotected under basic hydrolysis conditions to form compound R. Alkylation of compound R is carried out under basic conditions with an alkyl halide to form compound T.

Scenario 3

Referring to Scheme 3, nucleophilic substitution on chloride compound U is performed under basic conditions with a nucleophile WW'-NH such as an amine WW'-NH or an alcohol W-OH to form compound X. For example, compound U can be treated with DIEA and the amine WW'-NH. Biaryl compounds Z are prepared from aryl halide compounds X via a palladium-mediated cross-coupling reaction with a suitable coupling partner such as boronic acid YB(OH) ₂ . Compound Z is converted to compound AA by condensation with N,N-dimethylformamide dimethyl acetal. Compound AB is obtained from compound AA by reduction of the nitro group and ring condensation to form an indole ring system. Alkylation of compound AB is carried out under basic conditions with alkyl halide AC-X to form compound AD.

Scenario 4

Referring to Scheme 4, compound AE is brominated to yield compound AF. Compounds AF are selectively reduced by halogen-lithium exchange, eg, using one equivalent of n-LiBu, followed by quenching with an acidic aqueous solution. Compounds AG are converted to AH using nitrating conditions such as aqueous _HNO3 . Compound AH is chlorinated to yield compound AI. For example, chlorination can occur through the use of phosphorus oxychloride. Compound AJ is obtained from the selective reduction of compound AI, such as with iron in acetic acid. Compound AJ is converted to compound AL via a palladium-mediated cross-coupling reaction with a suitable coupling partner such as boronic acid AK-B(OH) ₂ . Compound AO is prepared from aryl halide compound AL via a palladium-mediated cross-coupling reaction with a suitable coupling partner such as boronic acid AM-B(OH) ₂ . Compound AO is acylated to give compound AP. This can be achieved by using acetic anhydride in the presence of pyridine. Compound AQ was obtained from treatment of Compound AP with isoamyl nitrite and acetic acid. Compound AQ is hydrolyzed under basic conditions to form compound AR. Alkylation of compound AR is carried out under basic conditions with an alkyl halide AS-C to form compound AT.

Scenario 5

Referring to Scheme 5, compound AW can be prepared by a palladium-catalyzed cross-coupling reaction of compound AU with a suitable coupling partner such as boronic acid AV-B(OH) ₂ at temperatures up to 100°C. The nucleophilic substitution reaction of compound AW with amine AX-NH-AX' under basic conditions at 100 °C affords AY. Palladium-catalyzed cross-coupling of AY with a suitable coupling partner such as boronic acid AZ-B(OH) ₂ at elevated temperatures up to 120°C provides pyrimidine BA. Alternatively, subjecting compound AY to a terminal alkyne such as BB-CCH under Sonogashira cross-coupling conditions provides compound BC.

Option 6

Referring to Scheme 6, compound BE was condensed with monosubstituted hydrazine BF- _NHNH2 to form compound BG. Compound BG is hydrolyzed under basic conditions to yield compound BH. Compound BH was converted to compound BI by Curtius rearrangement using diphenylphosphorazidate (DPPA). Alkylation of compound BI is carried out under basic conditions with various electrophiles such as alkyl halides, alkyl methanesulfonates, tosylates, or the like to form compounds BK. Compound BK is deprotected under acidic conditions to form compound BL.

Option 7

Referring to Scheme 7, compound BN was prepared from the nucleophilic substitution reaction of compound BM with amine AX-NH-AX' under basic conditions. Palladium-catalyzed cross-coupling reaction of compound BN with a suitable coupling partner such as boronic acid AV-B(OH) ₂ provides compound BP. Treatment with N-bromosuccinimide (NBS) provides compound BQ. Palladium-catalyzed cross-coupling of BQ with a suitable coupling partner such as boronic acid AZ-B(OH) ₂ provides pyrazine BR. Alternatively, subjecting compound BQ (or AY) to a terminal alkyne such as BB-CCH under Sonogashira cross-linking coupling conditions provides compound BS.

In each of the above reaction procedures or schemes, the various substituents can be selected from the various substituents otherwise taught herein.

pharmaceutical composition

In certain embodiments, the Substituted Heterocyclic Derivative Compounds as described herein are administered as neat chemicals. In other embodiments, the Substituted Heterocyclic Derivative Compounds described herein are based on a compound based on, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed., Mack Pub. Co., Easton, PA (2005)) (The disclosure of which is hereby incorporated by reference in its entirety) selected routes of administration and pharmaceutically suitable or acceptable carriers (also referred to herein as pharmaceutically suitable) selected by standard pharmaceutical practice (or acceptable) excipient, physiologically suitable (or acceptable) excipient or physiologically suitable (or acceptable) carrier) combination.

Accordingly, provided herein are pharmaceutical compositions comprising at least one Substituted Heterocyclic Derivative Compound, or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate, or N-oxide thereof substance and one or more pharmaceutically acceptable carriers. A carrier (or excipient) is acceptable or suitable if it is compatible with the other ingredients of the composition and is not injurious to the recipient (ie, subject) of the composition.

One embodiment provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

One embodiment provides a pharmaceutical composition comprising a compound of formula (II), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

One embodiment provides a pharmaceutical composition comprising a compound of formula (III), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

One embodiment provides a pharmaceutical composition comprising a compound of formula (IV), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

In certain embodiments, a Substituted Heterocyclic Derivative Compound as described by Formula (I), Formula (II), Formula (III), or Formula (IV) is substantially pure because it contains less than about 5 %, or less than about 1%, or less than about 0.1% of other small organic molecules, such as, for example, contaminating intermediates or by-products produced in one or more of the steps of a synthetic method.

Suitable oral dosage forms include, for example, tablets, pills, sachets or capsules of hard or soft gelatin, methylcellulose, or another suitable material that dissolves readily in the digestive tract. Suitable nontoxic solid carriers may be employed including, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, and the like. (See, eg, Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)).

Dosages of compositions comprising at least one Substituted Heterocyclic Derivative Compound as described herein may vary, depending on the condition of the patient (eg, human), ie, stage of disease, general health, age, and skill in the medical field Other factors that personnel will use to determine dosage.

The pharmaceutical composition can be administered in a manner suitable for the disease to be treated (or prevented) as determined by one of skill in the medical arts. Appropriate dosages and appropriate duration and frequency of administration will be determined by such factors as the patient's condition, the type and severity of the patient's disease, the particular form of active ingredient, and the method of administration. Generally, appropriate dosages and treatment regimens are sufficient to provide therapeutic benefit and/or prophylactic benefit (eg, improved clinical outcomes, such as more frequent complete or partial remissions, or longer disease-free) and/or overall survival, or reduction in symptom severity) to provide the composition. Optimal dosages can generally be determined using experimental models and/or clinical trials. The optimal dose may depend on the body mass, weight or blood volume of the patient.

Oral dosages may generally range from about 1.0 mg to about 1000 mg once to four or more times per day.

biology

Epigenetics is the study of inheritable changes in gene expression caused by mechanisms other than the underlying DNA sequence. Molecular mechanisms at play in epigenetic regulation include DNA methylation and chromatin/histone modifications.

The genomes of eukaryotic organisms are highly organized within the nucleus of the cell. A huge compaction is required to pack the 3 billion nucleotides of the human genome into the nucleus of a cell. Chromatin is the complex of DNA and proteins that make up chromosomes. Histones are the major protein components of chromatin, acting as spools around which DNA is wound. Changes in chromatin structure are influenced by covalent modifications of histone proteins and by non-histone-bound proteins. Several classes of enzymes are known that can modify histones at various sites.

There are a total of six classes of histones (H1, H2A, H2B, H3, H4 and H5) organized into two groups: core histones (H2A, H2B, H3 and H4) and linker histones (linker histone) (H1 and H5). The basic unit of chromatin is the nucleosome, which consists of about 147 base pairs of DNA wrapped around a core histone octamer consisting of the core histones H2A, H2B, H3 and Consists of two copies of each of H4.

The basic nucleosome units are then further organized and condensed through the aggregation and folding of nucleosomes to form a highly condensed chromatin structure. A range of different condensed states are possible, and the tightness of chromatin structure varies during the cell cycle and is most compact during the process of cell division.

Chromatin structure plays an important role in regulating gene transcription, which cannot occur efficiently from highly condensed chromatin. Chromatin structure is governed by a series of posttranslational modifications of histone proteins, especially histones H3 and H4, and most commonly within histone tails that extend beyond the core nucleosome structure. These modifications are acetylation, methylation, phosphorylation, ribosylation, sumoylation, ubiquitination, citrullination, deimination and biotinylation. The cores of histones H2A and H3 can also be modified. Histone modifications are an essential part of diversifying biological processes such as gene regulation, DNA repair and chromosome condensation.

Histone methylation is one of the most important chromatin markers; they play important roles in transcriptional regulation, DNA damage response, heterochromatin formation and maintenance, and X chromosome inactivation. Recent discoveries have also revealed that histone methylation affects the outcome of pre-mRNA splicing by affecting the recruitment of splicing regulators. Histone methylation includes mono-, di-, and tri-methylation of lysine, and mono-, symmetric, and asymmetric dimethylation of arginine. These modifications can be markers of activation or inhibition, depending on the site and degree of methylation.

histone demethylase

As referred to herein as a "demethylase" or "protein demethylase" refers to an enzyme that removes at least one methyl group from a polypeptide. The demethylase contains the JmjC domain and can be a methyl-lysine demethylase or a methyl-arginine demethylase. Certain demethylases act on histones, for example, acting as histone H3 demethylases or H4 demethylases. For example, an H3 demethylase can demethylate one or more of H3K4, H3K9, H3K27, H3K36, and/or H3K79. Alternatively, H4 demethylases can demethylate histone H4K20. Demethylases are known to demethylate monomethylated, dimethylated and/or trimethylated substrates. In addition, histone demethylases can act on methylated core histone substrates, mononucleosome substrates, dinucleosome substrates and/or oligonucleosome substrates, peptide substrates and/or stains quality (eg, in cell-based assays).

The first lysine demethylase discovered was lysine-specific demethylase 1 (LSD1/KDM1), which uses flavin as a cofactor to mono- and di-methylated H3K4 or Both H3K9 are demethylated. A second class of Jumonji C (JmjC) domain-containing histone demethylases was predicted and confirmed when H3K36 demethylases were discovered using a formaldehyde release assay, which was named JmjC domain-containing histone demethylases Base enzyme 1 (JHDM1/KDM2A).

Subsequently, more proteins containing the JmjC domain were identified, and they could be phylogenetically clustered into seven subfamilies: JHDM1, JHDM2, JHDM3, JMJD2, JARID, PHF2/PHF8, UTX/UTY, and JmjC domains only.

LSD-1

Lysine-specific demethylase 1 (LSD1) is a histone lysine demethylase that methylates monomethylated histones H3 and dimethylated histones at K4. Methylated histone H3 is specifically demethylated, and dimethylated histone H3 is also demethylated at K9. Although the primary targets of LSD1 appear to be monomethylated and dimethylated histone lysines, especially H3K4 and H3K9, the presence of LSD1 in the literature can enable the use of non-histone proteins such as p53 Evidence for demethylation of methylated lysines on E2F1, Dnmt1 and STAT3.

LSD1 has a considerable degree of structural similarity and amino acid identity/homology to polyamine oxidase and monoamine oxidase, all of which (ie, MAO-A, MAO-B and LSD1) are catalytic nitrogen - Flavin-dependent amine oxidase for the oxidation of hydrogen bonds and/or nitrogen-carbon bonds. LSD1 also contains an N-terminal SWRIM domain. There are two transcript variants of LSD1 produced by alternative splicing.

Instructions

In certain embodiments, the compounds disclosed herein are capable of inhibiting LSD1 activity in a biological sample by contacting the biological sample with a substituted heterocyclic compound as disclosed herein. In certain embodiments, substituted heterocyclic compounds as disclosed herein are capable of modulating the level of histone 4 lysine 3 methylation in a biological sample. In certain embodiments, substituted heterocyclic compounds as disclosed herein are capable of modulating levels of histone-3 lysine-9 methylation in biological samples.

In certain embodiments, substituted heterocyclic compounds as disclosed herein inhibit LSD1 activity to a greater extent than MAO-A and/or MAO-B.

One embodiment provides a method of modulating gene transcription in a cell, the method comprising inhibiting a lysine-specific demethylase 1 enzyme by exposing the lysine-specific demethylase 1 enzyme to a compound of formula (I) 1 active.

One embodiment provides a method of modulating gene transcription in a cell, the method comprising inhibiting a lysine-specific demethylase 1 enzyme by exposing the lysine-specific demethylase 1 enzyme to a compound of formula (II) 1 active.

One embodiment provides a method of modulating gene transcription in a cell, the method comprising inhibiting a lysine-specific demethylase 1 enzyme by exposing the lysine-specific demethylase 1 enzyme to a compound of formula (III) 1 active.

One embodiment provides a method of modulating gene transcription in a cell, the method comprising inhibiting a lysine-specific demethylase 1 enzyme by exposing the lysine-specific demethylase 1 enzyme to a compound of formula (IV) 1 active.

treatment method

Disclosed herein are methods of modulating demethylation in a cell or in a subject in general or with respect to one or more specific target genes. Demethylation can be modulated to control various cellular functions, including, but not limited to: differentiation; proliferation; apoptosis; tumorigenesis, leukemogenesis, or other oncogenic transformation events; alopecia; or sex differentiation.

One embodiment provides a method of treating cancer in a patient in need thereof, the method comprising administering to the patient a compound of formula (I) or a pharmaceutically acceptable salt thereof.

One embodiment provides a method of treating cancer in a patient in need thereof, the method comprising administering to the patient a compound of formula (II) or a pharmaceutically acceptable salt thereof.

One embodiment provides a method of treating cancer in a patient in need thereof, the method comprising administering to the patient a compound of formula (III) or a pharmaceutically acceptable salt thereof.

One embodiment provides a method of treating cancer in a patient in need thereof, the method comprising administering to the patient a compound of formula (IV) or a pharmaceutically acceptable salt thereof.

In additional embodiments are methods for treating cancer in a subject, wherein the cancer is selected from prostate cancer, breast cancer, bladder cancer, lung cancer, or melanoma.

Other embodiments and uses will be apparent to those skilled in the art in view of this disclosure. The following examples are offered merely as illustrations of various embodiments, and should not be construed as limiting the invention in any way.

Example

I. Chemical synthesis

Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. Anhydrous solvents and oven-dried glassware were used for moisture- and/or oxygen-sensitive synthetic transformations. Yield is not optimized. Reaction times are approximate and not optimized. Column chromatography and thin layer chromatography (TLC) were performed on silica gel unless otherwise noted. Spectra are given in ppm (δ) and coupling constants, J, are reported in Hertz. For proton spectroscopy, the solvent peak was used as the reference peak.

Preparation 1A: 1-(Benzenesulfonyl)-6-bromopyrrolo[3,2-b]pyridine

To a solution of NaH (1.13 g, 28.05 mmol, 60%) in THF (50 mL) at 0 °C was added 6-bromo-1H-pyrrolo[3,2-b]pyridine (5 g in small portions) , 25.5 mmol). The reaction mixture was stirred for 15 minutes. Then, a solution of benzenesulfonyl chloride (4.86 g, 25.5 mmol) in THF (40 mL) was added dropwise at 0 °C. The resulting solution was stirred at room temperature for 18 hours. The reaction mixture was quenched by adding 50 mL of _H2O . The mixture was concentrated and the resulting solution was extracted with EtOAc (3x). The organic layers were combined, dried ( _{Na2SO4 )} and concentrated in vacuo to give 8.54 g (99%) of the title compound as a beige solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 7.01 (d, J=3.79 Hz, 1H), 7.60-7.69 (m, 2H), 7.71-7.81 (m, 1H), 8.09-8.16 (m, 2H) ), 8.22 (d, J=3.79Hz, 1H), 8.45-8.51 (m, 1H), 8.64 (d, J=2.02Hz, 1H). [M ₊ H] _calcd for _{C13H9BrN2O2S 337,339} ; found 337,339.

Preparation 1B: 6-Bromo-1-(phenylsulfonyl)-1H-pyrrolo[3,2-b]pyridine-4-oxide

To a stirred solution of 6-bromo-1-(phenylsulfonyl)-1H-pyrrolo[3,2-b]pyridine (8.54 g, 25.4 mmol) in DCM (120 mL) at 0 °C was added 3 - Chloroperbenzoic acid (77 wt%, 6.83 g, 30.49 mmol). The reaction mixture was stirred at room temperature overnight. The solution was washed with saturated aqueous _NaHCO3 (2x). The organics were dried ( _{Na2SO4 )} and concentrated in vacuo. The residue was chromatographed (0-15%, MeOH:DCM) to provide 6.34 g (71%) of the title compound as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ )δ7.05-7.09(m,1H), 7.64-7.71(m,2H), 7.76-7.84(m,1H), 8.08(s,1H), 8.12-8.18 (m, 3H), 8.57 (d, J=1.26Hz, 1H). [ _M +H] _calcd for _{C13H9BrN2O3S 354,356} ; found 354,356.

Preparation 1C: 1-(Benzenesulfonyl)-6-bromo-5-chloropyrrolo[3,2-b]pyridine

A solution of phosphorus oxychloride (1.43 mL, 15.3 mmol) in DCM (8 mL) was added dropwise to 6-bromo-1-(phenylsulfonyl)-1H-pyrrolo[3, A mixture of 2-b]pyridine-4-oxide (4.50 g, 12.8 mmol) and triethylamine (2.13 mL, 15.3 mmol) in DCM (40 mL). The reaction mixture was stirred at 0°C for 1 hour and then at room temperature for 3 hours. The mixture was quenched with water (100 mL). The organic layer was separated, washed with saturated _NaHCO3 solution, brine, dried ( _{Na2SO4 )} and concentrated in vacuo. The residue was chromatographed (0-5%, MeOH:DCM) to provide 2.23 g (47%) of the title compound as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ )δ7.00(d, J=3.79Hz, 1H), 7.61-7.69(m, 2H), 7.74-7.80(m, 1H), 8.14(d, J=7.33 Hz, 2H), 8.31 (d, J=3.79 Hz, 1H), 8.65 (s, 1H). [M ₊ H] _calcd for _{C13H8BrClN2O2S 373,375} ; found 373,375.

Preparation 1D: 4-[1-(Benzenesulfonyl)-5-chloropyrrolo[3,2-b]pyridin-6-yl]benzonitrile

To 1-(benzenesulfonyl)-6-bromo-5-chloropyrrolo[3,2-b]pyridine (2.23 g, 6.04 mmol), Pd(dppf)Cl2 (0.25 _g , 0.30 mmol), sodium carbonate To a mixture of aqueous solution (2.0 M, 10 mL) in dioxane (40 mL) was added 4-cyanophenylboronic acid (0.98 g, 6.64 mmol). The reaction mixture was stirred and heated at reflux for 30 minutes. Evaporate the solvent. The residue was taken up in water and extracted with DCM (3x). The organic layers were combined, washed with brine, dried ( _{Na2SO4 )} and concentrated in vacuo. The residue was chromatographed (0-5%, MeOH:DCM) to give 1.79 g (75%) of the title compound as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 7.06 (d, J=3.79 Hz, 1H), 7.60-7.67 (m, 2H), 7.73-7.79 (m, 3H), 8.01 (d, J=8.34 Hz, 2H), 8.12 (d, J=7.58 Hz, 2H), 8.31 (s, 1H), 8.35 (d, J=3.79 Hz, 1H). _{[ M} +H] _calcd for _{C20H12ClN3O2S} 394; found 394.

Preparation 1E: 4-(5-Chloro-1H-pyrrolo[3,2-b]pyridin-6-yl)benzonitrile

To 4-[1-(benzenesulfonyl)-5-chloropyrrolo[3,2-b]pyridin-6-yl]benzonitrile (1.18 g, 3.00 mmol) in MeOH:THF (3:2, 50 mL) ) was added NaOH (2.5N, 12 mL). The reaction mixture was stirred at room temperature for 15 minutes. The reaction was acidified (2N HCl) and extracted with DCM (3x). The organics were combined and washed with brine, dried ( _{Na2SO4 )} and concentrated in vacuo. The residue was triturated in DCM (20 mL) and filtered to give 580 mg (76%) of the title compound as a yellow solid. ¹ H NMR (400MHz, DMSO-d ₆ )δ6.60(br.s.,1H),7.72(d,J=8.34Hz,2H),7.81(t,J=2.91Hz,1H),7.85(s , 1H), 7.95 (d, J=8.34Hz, 2H), 11.68 (br.s., 1H). [ _M +H] _calcd for _C14H8ClN3 254; found 254.

Preparation 1F: (3S)-3-[[5-Chloro-6-(4-cyanophenyl)pyrrolo[3,2-b]pyridin-1-yl]methyl]pyrrolidine-1-carboxylic acid tert-butyl ester

(R)-N-boc-3-bromomethylpyrrolidine (96 mg, 0.37 mmol) was added to 4-(5-chloro-1H-pyrrolo[3,2-b]pyridin-6-yl)benzyl A mixture of nitrile (100 mg, 0.33 mmol) and cesium carbonate (214 mg, 0.65 mmol) in DMF (3 mL). The reaction mixture was stirred at 90°C overnight. (R)-N-Boc-3-bromomethylpyrrolidine (96 mg, 0.37 mmol) was added and the reaction was stirred at 90°C for 2 hours. DMF was concentrated in vacuo. The residue was taken up in DCM and the insoluble solid was filtered off. The filtrate was loaded on a silica column and chromatographed (0-100%, EtOAc:hexanes) to give 125 mg (77%) of the title compound as a colorless oil. ¹ H NMR (400MHz, DMSO-d ₆ )δ1.25-1.45(m, 9H), 1.59(br.s., 1H), 1.76(br.s., 1H), 2.67(br.s., 2H) ), 2.89-3.05(m, 1H), 3.08-3.30(m, 2H), 4.18-4.39(m, 2H), 6.63(d, J=3.03Hz, 1H), 7.75(d, J=8.34Hz, 2H), 7.87 (d, J=3.28Hz, 1H), 7.97 (d, J=8.34Hz, 2H), 8.21 (d, J=2.78Hz, 1H). _{[ M} +H] _calcd for _C24H25ClN3O2 437; found 437.

Preparation 1G: (3S)-3-[[6-(4-cyanophenyl)-5-(4-methylphenyl)pyrrolo[3,2-b]pyridin-1-yl]methyl] Pyrrolidine-1-carboxylate tert-butyl ester

tert-butyl to (3S)-3-[[5-chloro-6-(4-cyanophenyl)pyrrolo[3,2-b]pyridin-1-yl]methyl]pyrrolidine-1-carboxylate A mixture of ester (100 mg, 0.23 mmol), Pd(dppf)Cl2 ( ₁₀ mg, 0.012 mmol), aqueous sodium carbonate (2.0 M, 1.0 mL, 2.00 mmol) in dioxane (2 mL) was added 4-methyl Phenylboronic acid (50 mg, 0.36 mmol). The reaction mixture was stirred and heated in the microwave at 143°C for 1 hour. The solvent was evaporated in vacuo. The residue was taken up in DCM and filtered. The filtrate was chromatographed (0-90%, EtOAc:Hexanes) to give 90 mg (79%) of the title compound as a beige solid. [M ₊ H] _calcd for _C31H32N4O2 493 _; found 493.

Example 1: 4-[5-(4-Methylphenyl)-1-[[(3R)-pyrrolidin-3-yl]methyl]pyrrolo[3,2-b]pyridin-6-yl ] benzonitrile

To (3S)-3-[[6-(4-cyanophenyl)-5-(4-methylphenyl)pyrrolo[3,2-b]pyridin-1-yl]methyl]pyrrolidine - To a mixture of tert-butyl 1-carboxylate (90 mg, 0.18 mmol) in DCM (2 mL) was added TFA (2 mL). The reaction was stirred for 30 minutes. The solvent was evaporated in vacuo. The residue was chromatographed (0-20%, MeOH:DCM) to give 56 mg (78%) of the TFA salt of the title compound as a beige solid. ¹ H NMR (400MHz, DMSO-d ₆ )δ1.61-1.77(m,1H), 1.84-2.01(m,1H), 2.29(s,3H), 2.76-3.01(m,3H), 3.02-3.16 (m,1H),3.24-3.37(m,2H),4.29-4.49(m,2H),6.72(d,J=3.03Hz,1H),7.05-7.14(m,2H),7.14-7.20(m ,2H),7.42(d,J＝8.34Hz,2H),7.80(d,J＝8.34Hz,2H),7.91(br.s.,1H),8.23(br.s.,1H),8.60- 8.85 (m, 2H). [ _{M +} H] calcd for _C26H24N4 393; found 393.

Example 2: 4-[5-Chloro-1-[[(3R)-pyrrolidin-3-yl]methyl]pyrrolo[3,2-b]pyridin-6-yl]benzonitrile

tert-butyl to (3S)-3-[[5-chloro-6-(4-cyanophenyl)pyrrolo[3,2-b]pyridin-1-yl]methyl]pyrrolidine-1-carboxylate A mixture of ester (50 mg, 0.11 mmol) in DCM (3 mL) was added TFA (1 mL). The reaction was stirred for 2 hours. The solvent was evaporated in vacuo. The residue was chromatographed (0-20%, MeOH:DCM) to give 35 mg (96%) of the TFA salt of the title compound as a yellow glassy solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 1.56-1.71 (m, 1H), 1.90 (td, J=12.69, 7.20Hz, 1H), 2.72-2.93 (m, 3H), 3.05-3.15 (m ,1H),3.21-3.30(m,1H),4.32(dd,J＝7.20,4.42Hz,2H),6.66(d,J＝3.28Hz,1H),7.74(d,J＝8.34Hz,2H) , 7.90 (d, J=3.03Hz, 1H), 7.99 (d, J=8.34Hz, 2H), 8.24 (s, 1H), 8.62 (br.s., 2H). [M ₊ H] _calcd for _C19H17ClN4 337; found 337.

Preparation 3A: 4-[1-(Benzenesulfonyl)-5-(4-methylphenyl)pyrrolo[3,2-b]pyridin-6-yl]benzonitrile

To 4-[1-(benzenesulfonyl)-5-chloropyrrolo[3,2-b]pyridin-6-yl]benzonitrile (300 mg, 0.76 mmol), Pd(dppf)Cl2 (31 _mg , 0.038 mmol), aqueous sodium carbonate (2.0 M, 1.15 mL, 2.28 mmol) in dioxane (7 mL) was added 4-methylphenylboronic acid (310 mg, 2.28 mmol). The reaction mixture was stirred and heated in the microwave at 135°C for 3 hours. The solvent was evaporated in vacuo. The residue was taken up in water and extracted with DCM. The organics were combined and washed with brine, dried ( _{Na2SO4 )} and concentrated in vacuo. The residue was chromatographed (0-5%, MeOH:DCM) to give 260 mg (47%) of the title compound as a beige solid. [ _{M +} H] _calcd for _C27H19N3O2S 450; found 450.

Preparation 3B: 4-[5-(4-Methylphenyl)-1H-pyrrolo[3,2-b]pyridin-6-yl]benzonitrile

To 4-[1-(benzenesulfonyl)-5-(4-methylphenyl)pyrrolo[3,2-b]pyridin-6-yl]benzonitrile (260 mg, 0.58 mmol) in MeOH:THF (2:1, 15 mL) was added NaOH (2.5N, 3 mL). The reaction mixture was stirred at room temperature for 3 hours. The reaction was neutralized with aqueous HCl, and the solvent was evaporated. The residue was taken up in water and extracted with DCM. The organics were combined and washed with brine, dried ( _{Na2SO4 )} and concentrated in vacuo. The residue was chromatographed (0-5%, MeOH:DCM). The relevant fractions were combined and concentrated to provide 90 mg (49%) of the title compound as a beige solid. [ _M +H] _calcd for _C21H15N3 310; found 310.

Preparation 3C: (3R)-3-[[6-(4-Cyanophenyl)-5-(4-methylphenyl)pyrrolo[3,2-b]pyridin-1-yl]methyl] Pyrrolidine-1-carboxylate tert-butyl ester

(S)-N-Boc-3-bromomethylpyrrolidine (137 mg, 0.52 mmol) was added to 4-[5-(4-methylphenyl)-1H-pyrrolo[3,2-b]pyridine A mixture of -6-yl]benzonitrile (80 mg, 0.26 mmol) and cesium carbonate (422 mg, 1.30 mmol) in DMF (3 mL). The reaction mixture was stirred at 90°C overnight. The DMF was removed in vacuo. The residue was taken up in DCM and the insoluble solid was filtered off. The filtrate was loaded on a silica column and chromatographed (0-10%, MeOH:DCM) to give 45 mg (35%) of the title compound as a colorless oil. [M ₊ H] _calcd for _C31H32N4O2 493 _; found 493.

Example 3: 4-[5-(4-Methylphenyl)-1-[[(3S)-pyrrolidin-3-yl]methyl]pyrrolo[3,2-b]pyridin-6-yl ] benzonitrile

To (3R)-3-[[6-(4-cyanophenyl)-5-(4-methylphenyl)pyrrolo[3,2-b]pyridine-1- in ethanol (2 mL) tert-butyl]methyl]pyrrolidine-1-carboxylate (45 mg, 0.09 mmol) was added to HCl in dioxane (4N, 1 mL). The reaction was stirred for 2 hours and the solvent was evaporated. The residue was chromatographed (0-20%, MeOH:DCM) to give 30 mg (84%) of the HCl salt of the title compound as a beige solid. ¹ H NMR (400MHz, DMSO-d ₆ )δ1.60-1.77(m,1H), 1.89-2.01(m,1H), 2.32(s,3H), 2.80-3.02(m,3H), 3.24-3.37 (m,2H),4.48(br.s.,2H),6.82(br.s.,1H),7.12-7.29(m,4H),7.45(d,J=8.34Hz,2H),7.84(d , J=8.08Hz, 2H), 8.18 (s, 1H), 8.63 (s, 1H), 9.02 (br.s., 1H), 9.28 (br.s., 1H). [ _{M +} H] calcd for _C26H24N4 393; found 393.

Preparation 4A: (3R)-3-[[5-Chloro-6-(4-cyanophenyl)pyrrolo[3,2-b]pyridin-1-yl]methyl]pyrrolidine-1-carboxylic acid tert-butyl ester

The title compound was prepared in 25% yield from (S)-N-boc-3-bromomethylpyrrolidine and added to 4-(5-chloro-1H-pyrrolo[3] according to the procedure for the preparation of 3C. ,2-b]pyridin-6-yl)benzonitrile mixture. _{[ M} +H] _calcd for _C24H25ClN3O2 437; found 437.

Example 4: 4-[5-Chloro-1-[[(3S)-pyrrolidin-3-yl]methyl]pyrrolo[3,2-b]pyridin-6-yl]benzonitrile

The title compound was prepared according to the procedure for Example 3 from (3R)-3-[[5-chloro-6-(4-cyanophenyl)pyrrolo[3,2-b]pyridin-1-yl]pyrrolidine- 1-Carboxylic acid tert-butyl ester was prepared as the HCl salt in 90% yield. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 1.56-1.71 (m, 1H), 1.84-1.95 (m, 1H), 2.71-2.92 (m, 2H), 3.04-3.23 (m, 3H), 4.23 -4.39(m, 2H), 6.66(d, J=3.28Hz, 1H), 7.74(d, J=8.59Hz, 2H), 7.90(d, J=3.28Hz, 1H), 7.99(d, J= 8.59Hz, 2H), 8.24(s, 1H), 8.63(br.s., 1H), 8.73(br.s., 1H). [M ₊ H] _calcd for _C19H17ClN4 337; found 337.

Preparation 5A: 4-[1-(Benzenesulfonyl)-5-(4-fluorophenyl)pyrrolo[3,2-b]pyridin-6-yl]benzonitrile

To 4-[1-(benzenesulfonyl)-5-chloropyrrolo[3,2-b]pyridin-6-yl]benzonitrile (1 g, 2.54 mmol), Pd(dppf)Cl2 (100 _mg , 0.13 mmol), aqueous sodium carbonate (2.0 M, 3.31 mL, 7.62 mmol) in dioxane (10 mL) was added 4-fluoro-phenylboronic acid (1.42 g, 10.16 mmol). The reaction mixture was stirred and heated in the microwave at 143°C for 4 hours. The crude reaction mixture was used without purification in the next step. [ _{M +} H] _calcd for _C26H16FN3O2S 454; found 454.

Preparation 5B: 4-[5-(4-Fluorophenyl)-1H-pyrrolo[3,2-b]pyridin-6-yl]benzonitrile

To a mixture of crude 4-[1-(benzenesulfonyl)-5-(4-fluorophenyl)pyrrolo[3,2-b]pyridin-6-yl]benzonitrile (2.54 mmol) was added MeOH (10 mL) and NaOH (2.5N, 6 mL). The reaction mixture was stirred at room temperature for 5 hours. The reaction was extracted with DCM. The organics were combined and washed with brine, dried ( _{Na2SO4 )} and concentrated in vacuo. The residue was chromatographed (0-5%, MeOH:DCM). The relevant fractions were combined and concentrated to provide 480 mg (60%) of the title compound as a beige solid. [M+H] calculated for C ₂₀ H ₁₂ FN ₃ 314; found 314.

Preparation 5C: (3R)-3-[[6-(4-Cyanophenyl)-5-(4-fluorophenyl)pyrrolo[3,2-b]pyridin-1-yl]methyl]pyrrole tert-Butyl alkane-1-carboxylate

From 4-[5-(4-fluorophenyl)-1H-pyrrolo[3,2-b]pyridin-6-yl]benzonitrile and (R)-N-boc- 3-Bromomethylpyrrolidine prepared the title compound in 100% yield. [M ₊ H] _calcd for _{C30H29FN4O2 497} ; found 497.

Example 5: 4-[5-(4-Fluorophenyl)-1-[[(3S)-pyrrolidin-3-yl]methyl]pyrrolo[3,2-b]pyridin-6-yl] benzonitrile

The title compound was prepared according to the procedure used to prepare Example 3 from N-[3-[6-(4-cyanophenyl)-5-(4-methylphenyl)pyrrolo[3,2-b]pyridine- tert-Butyl 1-yl]propyl]carbamate was prepared as the HCl salt in 14% yield. ¹ H NMR (400 MHz, DMSO-d ₆ ): δppm 1.68-1.92 (m, 2H) 1.96-2.23 (m, 2H) 2.99-3.18 (m, 1H) 3.25-3.34 (m, 1H) 3.95 (d, J) =7.07Hz,1H)4.67(br.s.,2H)6.78(d,J=3.03Hz,1H)7.16(t,J=8.08Hz,2H)7.26-7.38(m,2H)7.44(d,J =8.34Hz,3H)7.83(d,J=8.34Hz,2H)8.04(br.s.,1H)8.38(br.s.,1H)8.95-9.34(m,2H). [M ₊ H] _calcd for _C25H21FN4 397; found 397.

Preparation 6A: 4-(3-Bromo-6-methyl-5-nitropyridin-2-yl)morpholine

To a mixture of 3-bromo-2-chloro-6-methyl-5-nitropyridine (2.00 g, 8.0 mmol) and morpholine (700 μL, 8.0 mmol) in DCM (20 mL) was added DIEA (1.40 mL, 8.0 mmol). The reaction mixture was stirred at room temperature for 16 hours. The solvent was evaporated. The residue was chromatographed (0-5%, MeOH:DCM) to give 2.21 g (92%) of the title compound as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.66 (s, 3H), 3.57-3.63 (m, 4H), 3.70-3.75 (m, 4H), 8.54 (s, 1H). Calculated for _{C10H12BrN3O3 303,305 ;} found _303,305 .

Preparation 6B: 4-(6-Methyl-2-morpholin-4-yl-5-nitropyridin-3-yl)benzonitrile

To 3-bromo-6-methyl-2-morpholinyl-5-nitropyridine (2.21 g, 7.34 mmol), Pd(dppf)Cl2 (0.31 _g , 0.37 mmol) and aqueous sodium carbonate (2.0 M, 5 mL) in dioxane (15 mL) was added 4-cyanophenylboronic acid (1.30 g, 8.08 mmol). The reaction mixture was stirred and heated at 110°C for 1 hour. The solvent was evaporated and the residue was taken up in water and extracted with DCM (3x). The organic layers were combined, washed with brine, dried ( _{Na2SO4 )} and concentrated in vacuo. The residue was chromatographed (0-5%, MeOH:DCM) to give 2.15 g (90%) of the title compound as a yellow solid. [ _{M +} H] _calcd for _C17H16N4O3 325; found 325.

Preparation 6C: 4-[6-[(E)-2-(dimethylamino)vinyl]-2-morpholin-4-yl-5-nitropyridin-3-yl]benzonitrile

To 3-(4-cyanophenyl)-6-methyl-2-morpholino-5-nitropyridine (2.15 g, 7.14 mmol) in DMF (12 mL) was added N,N-dimethyl Formamide dimethyl acetal (5.6 mL, 42.8 mmol). The reaction mixture was stirred at room temperature for 30 minutes and heated at 100°C for 3 hours. The solvent was removed in vacuo to give 2.7 g (99%) of the title compound as a burgundy red solid. This residue was used without purification in the next step. [ _M +H] _calcd for _{C20H21N5O3 380} ; found 380.

Preparation 6D: 4-(5-Morpholin-4-yl-1H-pyrrolo[3,2-b]pyridin-6-yl)benzonitrile

4-[6-[(E)-2-(dimethylamino)vinyl]-2-morpholin-4-yl-5-nitropyridin-3-yl]benzonitrile (2.7 g, 7.14 g mmol) was dissolved in MeOH:DCM (200 mL, 1:10). Pd/C (10%w, 330 mg, 0.72 mmol) was added under nitrogen. The nitrogen atmosphere was replaced with hydrogen and the reaction was stirred at room temperature for 3 hours. The reaction mixture was filtered through Celite and concentrated in vacuo. The residue was analyzed by column chromatography (0-10%, MeOH:DCM) to give 1.41 g (65%) of the title compound as a beige solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 2.83-2.99 (m, 4H), 3.47-3.62 (m, 4H), 6.46 (t, J=2.15Hz, 1H), 7.58 (t, J=2.91 Hz, 1H), 7.65 (s, 1H), 7.85-7.98 (m, 4H), 11.25 (br.s., 1H). [M ₊ H] _calcd for _C18H16N4O 305; found 305.

Preparation 6E: (3S)-3-[[6-(4-Cyanophenyl)-5-morpholin-4-ylpyrrolo[3,2-b]pyridin-1-yl]methyl]pyrrolidine - 1-Carboxylic acid tert-butyl ester

To a solution of 4-(5-morpholin-4-yl-1H-pyrrolo[3,2-b]pyridin-6-yl)benzonitrile (100 mg, 0.33 mmol) in DMF (3 mL) was added (R )-N-boc-3-bromomethylpyrrolidine (96 mg, 0.37 mmol), followed by cesium carbonate (214 mg, 0.65 mmol), and the mixture was stirred at 90 °C overnight. (R)-N-Boc-3-bromomethylpyrrolidine (96 mg, 0.37 mmol) was added and the reaction was stirred at 90°C for 2 hours. The DMF was removed in vacuo. The residue was taken up in DCM and the insoluble solid was filtered off. The filtrate was loaded on a silica column and analyzed by column chromatography (0-100%, EtOAc:Hexanes) to provide 125 mg (77%) of the title compound as a pale yellow oil. [ _M +H] _calcd for _{C28H33N5O3 488} ; found 488.

Example 6: 4-[5-Morpholin-4-yl-1-[[(3R)-pyrrolidin-3-yl]methyl]pyrrolo[3,2-b]pyridin-6-yl]benzene Formonitrile

To (3S)-3-[[6-(4-cyanophenyl)-5-morpholin-4-ylpyrrolo[3,2-b]pyridin-1-yl] in ethanol (4 mL) Methyl]pyrrolidine-1-carboxylate tert-butyl ester (125 mg, 0.26 mmol) was added with HCl in dioxane (4N, 3 mL). The reaction was stirred for 2 hours. The solvent was evaporated in vacuo. The residue was analyzed by column chromatography (0-20%, MeOH:DCM) to give 71 mg (70%) of the title compound as HCl salt (HCl salt) as a pale yellow solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 2.73-2.87(m, 2H), 2.86-2.97(m, 4H), 3.05-3.15(m, 3H), 3.22-3.30(m, 2H), 3.54 (d, J=4.55Hz, 4H), 4.23-4.32 (m, 2H), 6.49 (d, J=3.03Hz, 1H), 7.70 (d, J=3.03Hz, 1H), 7.91-7.99 (m, 4H), 8.01 (s, 1H), 9.07 (br.s., 1H). [M+H] _calcd for _{C23H25N5O 388} ; found 388.

Preparation 7A: (3R)-3-[[6-(4-Cyanophenyl)-5-morpholin-4-ylpyrrolo[3,2-b]pyridin-1-yl]methyl]pyrrolidine - 1-Carboxylic acid tert-butyl ester

From (S)-N-boc-3-bromomethylpyrrolidine and 4-(5-morpholin-4-yl-1H-pyrrolo[3,2-b]pyridine-6 according to the procedure used to prepare 6E -yl)benzonitrile The title compound was prepared in 58% yield. ¹ H NMR (400MHz, DMSO-d ₆ )δ1.33(s,9H), 1.50-1.67(m,1H), 1.67-1.88(m,1H), 2.61-2.77(m,2H), 2.90(br .s.,4H),2.95-3.23(m,3H),3.54(br.s.,4H),4.23(d,J=7.58Hz,2H),6.46(d,J=2.80Hz,1H), 7.63 (d, J=2.78 Hz, 1H), 7.83-8.05 (m, 5H). [ _M +H] _calcd for _{C28H33N5O3 488} ; found 488.

Example 7: 4-[5-Morpholin-4-yl-1-[[(3S)-pyrrolidin-3-yl]methyl]pyrrolo[3,2-b]pyridin-6-yl]benzene Formonitrile

To (3R)-3-[[6-(4-cyanophenyl)-5-morpholin-4-ylpyrrolo[3,2-b]pyridin-1-yl] in ethanol (4 mL) Methyl]pyrrolidine-1-carboxylate tert-butyl ester (116 mg, 0.19 mmol) was added with HCl in dioxane (4N, 3 mL). The reaction was stirred for 2 hours. The solvent was evaporated in vacuo to give 81 mg (99%) of the HCl salt of the title compound as a pale yellow solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 1.53-1.73 (m, 1H), 1.83-1.97 (m, 1H), 2.72-2.91 (m, 2H), 2.92-3.03 (m, 4H), 3.06 -3.20(m,2H),3.21-3.38(m,1H),3.48-3.59(m,4H),4.25-4.39(m,2H),6.58(br.s.,1H),7.82(br.s ., 1H), 7.89-8.02 (m, 4H), 8.22 (br.s., 1H), 8.98 (br.s., 1H), 9.25 (br.s., 1H). [M+H] _calcd for _{C23H25N5O 388} ; found 388.

Preparation 8A: 3-[[6-(4-Cyanophenyl)-5-morpholin-4-ylpyrrolo[3,2-b]pyridin-1-yl]methyl]-3-fluoropyrrolidine - 1-Carboxylic acid tert-butyl ester

From 1-N-boc-3-bromomethyl-3-fluoropyrrolidine and 4-(5-morpholin-4-yl-1H-pyrrolo[3,2-b]pyridine according to the procedure used to prepare 6E -6-yl)benzonitrile The title compound was prepared in 79% yield. [ _M +H] _calcd for _{C28H32FN5O3 506} ; found 506.

Example 8: 4-[1-[(3-Fluoropyrrolidin-3-yl)methyl]-5-morpholin-4-ylpyrrolo[3,2-b]pyridin-6-yl]benzyl Nitrile

From 3-[[6-(4-cyanophenyl)-5-morpholin-4-ylpyrrolo[3,2-b]pyridin-1-yl]-3 according to the procedure used to prepare Example 6 - tert-butyl fluoropyrrolidine-1-carboxylate The title compound was prepared as the HCL salt in 88% yield. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 1.93-2.39(m, 2H), 2.89-3.03(m, 4H), 3.21-3.34(m, 2H), 3.35-3.48(m, 2H), 3.50 -3.60(m, 4H), 4.73-4.87(m, 2H), 6.60(d, J=2.78Hz, 1H), 7.68(br.s., 1H), 7.87-8.02(m, 4H), 8.09( br.s., 1H), 9.44 (br.s., 1H), 9.66 (br.s., 1H). [ _M +H] calcd for _{C23H24FN5O 406} ; found 406.

Preparation 9A: 3-[[6-(4-Cyanophenyl)-5-(4-methylphenyl)pyrrolo[3,2-b]pyridin-1-yl]methyl]-3-fluoro Pyrrolidine-1-carboxylate tert-butyl ester

From 1-N-boc-3-bromomethyl-3-fluoropyrrolidine and 4-[5-(4-methylphenyl)-1H-pyrrolo[3,2-b according to the procedure used to prepare 3C ]pyridin-6-yl]benzonitrile The title compound was prepared in 41% yield. [M ₊ H] _calcd for _C31H31FN4O2 511 _; found 511.

Example 9: 4-[1-[(3-Fluoropyrrolidin-3-yl)methyl]-5-(4-methylphenyl)pyrrolo[3,2-b]pyridin-6-yl] benzonitrile

According to the procedure used to prepare Example 3 from 3-[[6-(4-cyanophenyl)-5-(4-methylphenyl)pyrrolo[3,2-b]pyridin-1-yl] Methyl]-3-fluoropyrrolidine-1-carboxylate tert-butyl ester prepared the title compound as the HCl salt in 66% yield. ¹ HNMR(400MHz, DMSO-d ₆ )δ2.08(br.s.,1H),2.23-2.31(m,1H),2.32(s,3H),3.33(d,J=5.05Hz,4H), 4.77-5.15(m, 2H), 6.90(br.s., 1H), 7.17-7.29(m, 4H), 7.43(d, J=8.34Hz, 2H), 7.84(d, J=8.34Hz, 2H) ), 8.13 (br.s., 1H), 8.65 (br.s., 1H), 9.67 (br.s., 1H), 9.98 (br.s., 1H). [M ₊ H] _calcd for _C26H23FN4 411; found 411.

Preparation 10A: (2S)-2-[[6-(4-Cyanophenyl)-5-(4-methylphenyl)pyrrolo[3,2-b]pyridin-1-yl]methyl] Morpholine-4-carboxylate tert-butyl ester

(2R)-tert-butyl 2-(bromomethyl)morpholine-4-carboxylate (145 mg, 0.52 mmol) was added to 4-[5-(4-methylphenyl)-1H-pyrrolo[3 A mixture of ,2-b]pyridin-6-yl]benzonitrile (80 mg, 0.26 mmol) and cesium carbonate (422 mg, 1.30 mmol) in DMF (3 mL). The reaction mixture was stirred at 90°C overnight. The insoluble solid was filtered off and the DMF was concentrated in vacuo to give 282 mg (100%) of the title compound as a brown semisolid. This residue was used without purification in the next step. [ _{M +} H] _calcd for _C31H32N4O3 509; found 509.

Example 10: 4-[5-(4-Methylphenyl)-1-[[(2R)-morpholin-2-yl]methyl]pyrrolo[3,2-b]pyridin-6-yl ] benzonitrile

The title compound was prepared according to the procedure used to prepare Example 3 from (2S)-2-[[6-(4-cyanophenyl)-5-(4-methylphenyl)pyrrolo[3,2-b] Pyridin-1-yl]methyl]morpholine-4-carboxylate tert-butyl ester was prepared as the HCl salt in 36% yield. ¹ H NMR (400MHz, DMSO-d ₆ ): δppm 2.20-2.40 (m, 3H) 2.76 (d, J=11.37Hz, 1H) 2.91 (d, J=12.13Hz, 1H) 3.06-3.24 (m, 2H) )3.37(d,J=11.87Hz,2H)3.94(d,J=9.60Hz,2H)4.13(br.s.,1H)4.43-4.74(m,2H)6.84(br.s.,1H)7.14 -7.34(m,4H)7.39-7.54(m,2H)7.85(d,J=8.34Hz,2H)8.06(br.s.,1H)8.49-8.75(m,1H)9.25-9.67(m,2H) ). [ _{M +} H] calcd for _C26H24N4O 409; found 409.

Preparation 11A: (2S)-2-[[6-(4-Cyanophenyl)-5-(4-fluorophenyl)pyrrolo[3,2-b]pyridin-1-yl]methyl]meth Phosphaline-4-carboxylate tert-butyl ester

From 4-[5-(4-fluorophenyl)-1H-pyrrolo[3,2-b]pyridin-6-yl]benzonitrile and (2R)-2-(bromo Methyl)morpholine-4-carboxylate tert-butyl ester prepared the title compound in 100% yield. [ _{M +} H] _calcd for _C30H29FN4O3 513; found 513.

Example 11: 4-[5-(4-Fluorophenyl)-1-[[(2R)-morpholin-2-yl]methyl]pyrrolo[3,2-b]pyridin-6-yl] benzonitrile

The title compound was prepared according to the procedure used to prepare Example 3 from (2S)-2-[[6-(4-cyanophenyl)-5-(4-fluorophenyl)pyrrolo[3,2-b]pyridine -1-yl]methyl]morpholine-4-carboxylate tert-butyl ester was prepared as the HCl salt in 27% yield. ¹ HNMR(400MHz, DMSO-d ₆ )δppm 2.71-2.81(m,1H)2.92(d,J=11.62Hz,1H)3.15(d,J=13.14Hz,1H)3.35(d,J=12.88Hz, 1H)3.94(d,J=9.09Hz,2H)4.11(br.s.,1H)4.39-4.72(m,2H)6.80(br.s.,1H)7.12-7.29(m,2H)7.29-7.53 (m, 4H) 7.71-7.92 (m, 2H) 7.92-8.10 (m, 1H) 8.45 (br.s., 1H) 9.13-9.55 (m, 2H). [M ₊ H] _calcd for _C25H21FN4O 413; found 413.

Preparation 12A: N-[3-[6-(4-Cyanophenyl)-5-(4-methylphenyl)pyrrolo[3,2-b]pyridin-1-yl]propyl]carbamic acid tert-butyl ester

From 4-[5-(4-methylphenyl)-1H-pyrrolo[3,2-b]pyridin-6-yl]benzonitrile and N-(3-bromopropane) according to the procedure used to prepare 10A yl) tert-butyl carbamate The title compound was prepared in 100% yield. [M ₊ H] _calcd for _C29H30N4O2 466 _; found 466.

Example 12: 4-[1-(3-Aminopropyl)-5-(4-methylphenyl)pyrrolo[3,2-b]pyridin-6-yl]benzonitrile

The title compound was prepared according to the procedure used to prepare Example 3 from N-[3-[6-(4-cyanophenyl)-5-(4-methylphenyl)pyrrolo[3,2-b]pyridine- tert-Butyl 1-yl]propyl]carbamate was prepared as the HCl salt in 20% yield. ¹ H NMR (400MHz, DMSO-d ₆ ): δppm 2.05-2.21(m, 2H) 2.32(s, 3H) 2.78(d, J=5.81Hz, 2H) 4.51(br.s., 2H) 6.82(br .s.,2H)7.09-7.31(m,4H)7.46(d,J=8.34Hz,2H)7.84(d,J=8.34Hz,2H)7.98(br.s.,2H)8.16(br.s .,1H)8.62(s,1H). [M ₊ H] _calcd for _C24H22N4 366; found 366.

Preparation 13A: 3,5-Dibromo-6-methylpyridin-2-ol

A solution of 2-hydroxy-6-methyl-pyridine (27.4 g, 0.25 mol) in dry acetonitrile (300 mL) was added to a 1 L three-necked reaction flask packed with aluminum foil. NBS (89 g, 0.5 mol) was added portionwise to the mixture over 20 min at 0 °C. As the suspension was difficult to stir, additional dry acetonitrile (200 ml) was added and stirring was continued at 30°C for 1.5 hours. The suspension was filtered. The filter cake was washed well with methanol (50 mL x 3) and dried to give 58.6 g (88%) of the title compound as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.90 (s, 1H), 2.46 (s, 3H). [M+H] _calcd for _{C6H5Br2NO 268,270} ; found 268,270.

Preparation 13B: 3-Bromo-6-methylpyridin-2-ol

In a 2L three-necked reaction flask (flame dried), 3,5-dibromo-6-methylpyridin- ₂ -ol (51.6 g, 193 mmol) in dry THF (500 mL) was added under N Stir at room temperature. The mixture was cooled to -67°C. n-BuLi (178 mL, 445 mmol) was added dropwise over 1 hour maintaining the temperature below -60°C. The mixture was stirred at -60°C for 1.5 hours. Saturated aqueous _NH4Cl (100 mL) was added dropwise over 1 hour at a temperature between -65°C and -40°C. The reaction mixture was stirred at -40°C for 15 minutes, allowed to reach 25°C, and then stirred overnight. The mixture was concentrated to remove THF, and the aqueous layer was extracted with EtOAc (300 mL x 3). The combined organic layers were washed with brine (200 mL x ₂ ), dried over _Na2SO4 , filtered, concentrated, and purified by column chromatography on silica gel (10-50%, EtOAc:PE) to give as 6.07 g (17%) of the title compound as an off-white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ 12.94 (s, 1H), 7.72 (d, J=7.2Hz, 1H), 5.99 (d, J=7.2Hz, 1H), 2.37 (t, J=8.4Hz) , 3H). [M+H] calcd for _{C6H6BrNO 189,191} ; found 189,191.

Preparation 13C: 3-Bromo-6-methyl-5-nitropyridin-2-ol

In a 500 mL round bottom flask, 65% aqueous HNO ₃ was stirred at 0 °C and 3-bromo-6-methylpyridin-2-ol (5.7 g, 30.3 mmol) was introduced dropwise. The reaction mixture was stirred at room temperature for 3.5 hours. After pouring the mixture into ice water (200 mL), the aqueous layer was extracted with EtOAc (300 mL x 2). The combined organic layers were washed with water, brine (200 mL x ₂ ), dried over _Na2SO4 , filtered, concentrated, and purified by column chromatography on silica gel (25%, EtOAc:PE) to give the compound as 4.7 g (67%) of the title compound as an off-white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 12.85 (s, 3H), 8.66 (s, 1H), 2.86 (s, 1H). [ _{M +} H] Calculated for _{C6H5BrN2O3 235,237} ; found 235,237.

Preparation 13D: 3-Bromo-2-chloro-6-methyl-5-nitropyridine

In a 500 mL single round bottom flask, POCl ₃ (12 g, 78.1 mmol) was added dropwise to 3-bromo-6-methyl-5-nitropyridin-2-ol (4 g, 15.87 mmol). Then, the mixture was stirred under reflux for 7 hours. The reaction mixture was cooled to 30°C, poured into ice water and stirred for 10 minutes. Then, saturated _NaHCO3 solution (30 mL) was added. The aqueous layer was extracted with EtOAc (200 mL x 3). The combined organic layers were washed with water, brine (200 mL x ₂ ), dried over _Na2SO4 , filtered and concentrated to give 2.8 g (65%) of the title compound as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.55 (s, 1H), 2.83 (s, 3H).

Preparation 13E: 5-Bromo-6-chloro-2-methylpyridin-3-amine

To a solution of 3-bromo-2-chloro-6-methyl-5-nitropyridine (2.2 g, 8.7 mmol) in EtOH (100 mL) was added Fe (4.8 g, 85.7 mmol) and HOAc (300 mL). The mixture was stirred at 30°C for 13 hours. The solids were filtered, and the filtrate was concentrated in vacuo to remove EtOH and most of the HOAc. The remaining aqueous solution was extracted with DCM (100 mL x 3). The combined organic layers were washed with water, brine (100 mL x ₂ ), dried over _Na2SO4 , filtered and concentrated to give 1.66 g (86%) of the title compound as a brown solid. [M+H] _calcd for _{C6H6BrClN2 221,223} ; found 221,223.

Preparation 13F: 4-(5-Amino-2-chloro-6-methylpyridin-3-yl)benzonitrile

To a solution of 5-bromo-6-chloro-2-methylpyridin-3-amine (1.66 g, 7.48 mmol) in dioxane (50 mL) was added 4-cyanophenylboronic acid (1.2 g, 8.97 mmol) ), _Na2CO3 ( _2.5 g, 23.6 mmol), Pd(dppf)Cl2 (306 _mg , 0.37 mmol) and a few drops of water. The mixture was degassed under _N2 for 5 minutes and heated to 70 °C for 13 hours. The solids were filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (15-25%, EtOAc:PE) to afford 1.42 g (79%) of the title compound as a brown solid. [ _M +H] _calcd for _C13H10ClN3 244; found 244.

Preparation 13G: 4-[5-Amino-6-methyl-2-(4-methylphenyl)pyridin-3-yl]benzonitrile

To a solution of 4-(5-amino-2-chloro-6-methylpyridin-3-yl)benzonitrile (1.4 g, 5.76 mmol) in dioxane (50 mL) was added 4-(5-amino -2-Chloro-6-methylpyridin-3-yl)benzonitrile (1.1 g, 8.15 mmol), _Na2CO3 (2.2 _g , 20.7 mmol), Pd(dppf)Cl2 (0.8 _g , 1.09 mmol) ) and a few drops of water. The mixture was degassed under _N2 for 5 minutes and heated to 110 °C for 14 hours. The solids were filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (15-25%, EtOAc:PE) to afford 1.3 g (76%) of the title compound as a pale yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.54 (d, J=8.0 Hz, 2H), 7.26 (d, J=6.0 Hz, 2H), 7.12 (d, J=8.0 Hz, 2H), 7.02 (d, J=8.0Hz, 2H), 6.96(s, 1H), 3.77(s, 2H), 2.56(s, 3H), 2.30(s, 3H). [ _M +H] calcd for _{C20H17N3 300} ; found 300.

Preparation of 13H: N-[5-(4-cyanophenyl)-2-methyl-6-(4-methylphenyl)pyridin-3-yl]acetamide

To a solution of 4-[5-amino-6-methyl-2-(4-methylphenyl)-pyrazol-3-yl]-benzonitrile (1.3 g, 4.35 mmol) in DCM (50 mL) Pyridine (1.4 mL, 15 mmol) and _Ac2O (1.3 mL, 13 mmol) were added. The mixture was stirred at 30°C for 16 hours. Saturated aqueous sodium bicarbonate solution was added portionwise to the reaction mixture. The reaction mixture was stirred for 10 minutes. The aqueous layer was extracted with DCM (100 mL x 3). The combined organic layers were washed with water, brine, dried _{over Na2SO4} , filtered and concentrated in vacuo to give 1.3 g (86%) of the title compound as a yellow oil. [ _M +H] _calcd for _C22H19N3O 342; found 342.

Preparation 13I: 4-[1-Acetyl-5-(4-methylphenyl)pyrazolo[4,3-b]pyridin-6-yl]benzonitrile

To N-[5-(4-cyanophenyl)-2-methyl-6-(4-methylphenyl)pyridin-3-yl]acetamide (1.3 g, 3.81 mmol) in toluene (20 mL) To the solution in tert-butyl nitrite (630 mg, 6.1 mmol), _Ac2O (1.1 mL, 11.5 mmol) and KOAc (452 mg, 4.6 mmol) were added. The mixture was heated at 80°C for 2 hours and then cooled to room temperature. 10% _NaHCO3 (150 mL) was added, and the mixture was extracted with EtOAc (100 ml x 3). The combined organic layers were washed with water, _NaHCO3 , brine, dried _{over Na2SO4} , filtered and concentrated in vacuo to give 0.8 g (60%) of the title compound as a brown solid. [M ₊ H] _calcd for _C22H16N4O 353; found 353.

Preparation 13J: 4-[5-(4-Methylphenyl)-1H-pyrazolo[4,3-b]pyridin-6-yl]benzonitrile

To 4-[1-acetyl-5-(4-methylphenyl)pyrazolo[4,3-b]pyridin-6-yl]benzyl in THF/MeOH (30 mL, 2:1) Nitrile (0.8 g, 2.27 mmol) was added with NaOH (2.3 M, 3 mL). The resulting mixture was stirred at room temperature for 1 hour. The solvent was removed in vacuo. The residue was taken up in water (30 mL), and the aqueous layer was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with water, brine, dried _{over Na2SO4} and concentrated. The crude product was further purified by column chromatography (33%, EtOAc:PE) to give 0.41 g (58%) of the title compound as a yellow solid. ¹ H NMR (400 MHz, CD ₃ OD): δ 8.29 (s, 1H), 8.07 (s, 1H), 7.65 (d, J=8.0 Hz, 2H), 7.42 (d, J=8.0 Hz, 2H) , 7.19 (d, J=8.0Hz, 2H), 7.12 (d, J=8.0Hz, 2H), 2.33 (s, 3H). [ _{M +} H] calcd for _C20H14N4 311; found 311.

Preparation 13K: 3-[[6-(4-Cyanophenyl)-5-(4-methylphenyl)pyrazolo[4,3-b]pyridin-1-yl]methyl]pyrrolidine- 1-Carboxylic acid tert-butyl ester

To 4-[5-(4-methylphenyl)-1H-pyrazolo[4,3-b]pyridin-6-yl]benzonitrile (100 mg, 0.32 mmol) and 3-[(4-ethyl A solution of tert-butyl phenyl)sulfonyloxymethyl]pyrrolidine-1-carboxylate (185 mg, 0.52 mmol) in DMF (5 mL) was added potassium carbonate (209 mg, 0.96 mmol). Then, the mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc (20 mL) and water (20 mL). The aqueous layer was extracted with EtOAc (30 mL x 3). The combined organic layers were washed with water (20 mL x 2), brine, dried _{over Na2SO4} , filtered and concentrated. The residue was purified by prep-HPLC to give 66 mg (43%) of the title compound as a white solid. ¹ H NMR (CDCl ₃ , 400MHz): δ 8.32 (s, 1H), 7.71 (s, 1H), 7.57 (d, J=8.4 Hz, 2H), 7.35 (d, J=5.6 Hz, 2H), 7.18(d,J＝8.0Hz,2H),7.07(d,J＝8.0Hz,2H),4.41(d,J＝7.2Hz,2H),3.48-3.43(m,2H),3.34-3.32(m ,1H),3.18(t,J＝4.8Hz,1H),2.90-2.91(m,1H),2.33(s,3H),2.00-1.98(m,1H),1.75-1.73(m,1H), 1.42(s, 9H). [M ₊ H] _calcd for _{C30H31N5O2 494} ; found 494.

Example 13: 4-[5-(4-Methylphenyl)-1-(pyrrolidin-3-ylmethyl)pyrazolo[4,3-b]pyridin-6-yl]benzonitrile

A solution of hydrochloric acid in dioxane (4M, 3 mL) was added to 4-[5-(4-methylphenyl)-1-(pyrrolidin-3-ylmethyl)pyrazolo[4,3 -b]pyridin-6-yl]benzonitrile (66 mg, 0.13 mmol) The mixture was then stirred at room temperature for 30 minutes. The resulting mixture was concentrated to provide 49 mg (94%) of the title compound as a white solid. ¹ HNMR (CD ₃ OD, 400MHz): δ 9.10(s, 1H), 8.54(s, 1H), 7.73(d, J=8.0Hz, 2H), 7.56(d, J=8.0Hz, 2H), 7.35(d,J=8.0Hz,2H),7.28(d,J=8.0Hz,2H),4.87-4.85(m,2H),3.62-3.49(m,3H),3.29-3.17(m,2H) , 2.39(s, 3H), 2.28-2.24(m, 1H), 1.99-1.93(m, 1H). [M+H] _calcd for _{C25H23N5 394} ; found 394.

Preparation 14A: 4-[[6-(4-Cyanophenyl)-5-(4-methylphenyl)pyrazolo[4,3-b]pyridin-1-yl]methyl]piperidine- 1-Carboxylic acid tert-butyl ester

To 4-[5-(4-methylphenyl)-1H-pyrazolo[4,3-b]pyridin-6-yl]benzonitrile (80 mg, 0.26 mmol) and 4-(bromomethyl) To a solution of piperidine-4-carboxylate tert-butyl ester (138 mg, 0.49 mmol) in DMF (3 mL) was added potassium carbonate (120 mg, 0.55 mmol). The mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc (20 mL) and water (20 mL). The aqueous layer was extracted with EtOAc (30 mL x 3). The combined organic layers were washed with water (20 mL x 2), brine, dried _{over Na2SO4} , filtered and concentrated to give the title compound as a yellow oil. This oil was used without purification in the next step. [M ₊ H] _calcd for _{C31H33N5O2 508} ; found 508.

Example 14: 4-[5-(4-Methylphenyl)-1-(piperidin-4-ylmethyl)pyrazolo[4,3-b]pyridin-6-yl]benzonitrile

To 4-[[6-(4-cyanophenyl)-5-(4-methylphenyl)pyrazolo[4,3-b]pyridin-1-yl]methyl] at 0 °C tert-Butyl piperidine-1-carboxylate (76 mg, 0.15 mmol) was added hydrochloric acid in dioxane (4M, 4 mL) at 0 °C. The mixture was warmed to room temperature and stirring was continued for 30 minutes. The reaction mixture was concentrated and the residue was purified by prep-HPLC to afford 25 mg (41%) of the title compound as a white solid. ¹ H NMR (D ₂ O, 400MHz): δ 8.18 (s, 1H), 8.06 (s, 1H), 7.45 (d, J=8.4 Hz, 2H), 7.16 (d, J=8.0 Hz, 2H) ,6.94(s,4H),4.33(d,J＝6.8Hz,2H),3.31(d,J＝13.2Hz,2H),2.83(t,J＝10.4Hz,2H),2.24-2.23(m, 1H), 2.14 (s, 3H), 1.69 (d, J=11.6Hz, 2H), 1.47-1.29 (m, 2H). Calculated for _{C26H25N5 408 ;} found 408.

Preparation 15A: (1S,5R)-6-[[6-(4-cyanophenyl)-5-(4-methylphenyl)pyrazolo[4,3-b]pyridin-1-yl] Methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate tert-butyl ester

4-[5-(4-methylphenyl)-1H-pyrazolo[4,3-b]pyridin-6-yl]benzonitrile (100 mg, 0.32 mmol), (1S,5R)-6 -(Chloromethyl)-3-azabicyclo[3.1.0]hexane- ₃ -carboxylate tert-butyl ester (115 mg, 0.49 mmol) and K2CO3 (150 _mg , 0.69 mmol) in DMF (8 mL) The mixture was stirred at 60 °C overnight. The mixture was cooled down to room temperature and diluted with water (50 mL) and ethyl acetate (50 mL). The solution was extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with water (50 mL x 3) and brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by prep-HPLC to give 62 mg (38%) of the title compound as a white solid. ¹ H NMR (CDCl ₃ , 400MHz): δ 8.35 (s, 1H), 7.76 (s, 1H), 7.61 (d, J=7.8Hz, 2H), 7.36 (d, J=8.2Hz, 2H), 7.21(d,J=7.4Hz,2H),7.09(d,J=7.8Hz,2H),4.41-4.35(m,2H),3.63-3.61(m,1H),3.50-3.48(m,1H) , 3.37-3.36(m, 2H), 2.35(s, 3H), 1.62-1.67(m, 2H), 1.40(s, 9H), 1.26-1.14(m, 1H). [M ₊ H] _calcd for _{C31H31N5O2 506} ; found 506.

Example 15: 4-[1-[[(1S,5R)-3-azabicyclo[3.1.0]hex-6-yl]methyl]-5-(4-methylphenyl)pyrazolo [4,3-b]pyridin-6-yl]benzonitrile

To (1S,5R)-6-[[6-(4-cyanophenyl)-5-(4-methylphenyl)pyrazolo[4,3-b]pyridin-1-yl]methyl ]-3-Azabicyclo[3.1.0]hexane-3-carboxylate tert-butyl ester (62 mg, 0.12 mmol) in DCM (5 mL) was added hydrochloric acid in dioxane (4M, 2 mL) . Then, the mixture was stirred at room temperature for 30 minutes. The resulting mixture was concentrated to give 35 mg (72%) of the title compound as a yellow oil as HCl salt. ¹ H NMR (CD ₃ OD, 400MHz): δ 8.85 (s, 1H), 8.45 (s, 1H), 7.72 (d, J=6.9 Hz, 2H), 7.54 (d, J=7.4 Hz, 2H) ,7.24-7.31(m,4H),4.64(d,J＝6.4Hz,2H),3.61-3.59(m,4H),2.38(s,3H),2.08-2.10(m,2H),1.72-1.74 (m, 1H). [M+H] _calcd for _{C26H23N5 406} ; found 406.

Preparation 16A: 4-(2,5-Dichloropyrimidin-4-yl)benzonitrile

To a 100 mL pressure vessel loaded with 2,4,5-trichloropyrimidine (1.83 g, 10 mmol) in dioxane (20 mL) was added (4-cyanophenyl)boronic acid (1.47 g, 10 mmol), PdCl ₂ (dppf) (146 mg, 0.2 mmol) and _Na2CO3 ( ₁₀ mL, 2M). The mixture was purged with _N2 for 5 minutes and sealed. The reaction was maintained at 70°C with vigorous stirring for 1 hour. Water was added and the heterogeneous mixture was filtered. The filter cake was placed in ethanol, stirred for 10 minutes, filtered, and dried in vacuo to afford the title compound (2.2 g, 89%) as off-white crystals. [ _M +H] _calcd for _{C11H5N3Cl2 250} ; found 250.

Preparation 16B: (3R)-tert-butyl 3-({[5-chloro-4-(4-cyanophenyl)pyrimidin-2-yl]amino}methyl)pyrrolidine-1-carboxylate

To a vial containing 4-(2,5-dichloropyrimidin-4-yl)benzonitrile (496 mg, 2 mmol) in ethanol (5 mL) was added (3S)-3-(aminomethyl)pyrrolidine-1 - tert-butyl carboxylate (400 mg, 2 mmol) and DIEA (694 μL, 4 mmol). The reaction was stirred at 100°C for 16 hours. The reaction was concentrated in vacuo and the residue was purified by column chromatography (0-50% gradient of EtOAc in hexanes) to afford the title compound (743 mg, 90%) as a yellow amorphous solid. [ _{M +} H] _calcd for _C21H24N5O2Cl 414; found 414.

Example 16: 4-[5-(4-Methylphenyl)-2-{[(3S)-pyrrolidin-3-ylmethyl]amino}pyrimidin-4-yl]benzonitrile

To the compound loaded with (3R)-3-({[5-chloro-4-(4-cyanophenyl)pyrimidin-2-yl]amino}methyl)pyrrolidine- To a microwave vial of tert-butyl 1-carboxylate (206 mg, 0.5 mmol) was added (4-methylphenyl)boronic acid (136 mg, 1 mmol), _PdCl2 (dppf) (36 mg, 0.05 mmol) and _Na2CO3 ( ₁ mL). , 2M). The mixture was purged with N2 for ₂ minutes and sealed. The reaction was irradiated in the microwave at 120°C for 2 hours or kept on a heating block at 120°C for 16 hours for addition. Water was added and the mixture was extracted with EtOAc (3X). The combined organic layers _were dried over _Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (0-50% gradient of EtOAc in hexanes) to afford a yellow amorphous foam which was purified by prep-HPLC (ACN in water with 0.1% HCO _{2 )} . 75%-95% gradient in H) for further purification to afford (3R)-3-({[4-(4-cyanophenyl)-5-(4-methylphenyl) as a yellow amorphous foam ) pyrimidin-2-yl]amino}methyl)pyrrolidine-1-carboxylate tert-butyl ester. The foam was dissolved in DCM (2 mL) followed by dropwise addition of TFA (2 mL). The reaction was stirred at ambient temperature for 30 minutes and concentrated in vacuo to afford the TFA salt of the title compound as an off-white amorphous foam (109 mg, 47%). ¹ H NMR (400MHz, CDCl ₃ )δ1.79-1.95(m,1H), 2.12-2.29(m,1H), 2.35(s,3H), 2.78-2.93(m,1H), 3.12-3.26(m ,1H),3.26-3.49(m,3H),3.49-3.61(m,1H),3.61-3.70(m,1H),5.76-6.01(m,1H),6.88-7.02(m,2H),7.08 -7.18(m, 2H), 7.47-7.62(m, 4H), 8.09-8.29(m, 1H), 8.29-8.39(m, 1H). [M+H] _calcd for _{C23H23N5 370} ; found 370.

Example 17: 4-(5-Chloro-2-{[(3S)-pyrrolidin-3-ylmethyl]amino}pyrimidin-4-yl)benzonitrile

To (3R)-3-({[5-chloro-4-(4-cyanophenyl)pyrimidin-2-yl]amino}methyl)pyrrolidine-1-carboxylic acid dissolved in DCM (2 mL) tert-Butyl ester was added dropwise TFA (2 mL). The reaction was stirred at ambient temperature for 30 minutes and concentrated in vacuo to afford the TFA salt of the title compound as an off-white amorphous foam (59 mg, 47%). ¹ H NMR (400 MHz, CDCl ₃ -d): δppm 1.68-2.08 (m, 1H), 2.12-2.49 (m, 1H), 2.66-3.11 (m, 1H), 3.37-3.90 (m, 6H), 7.67 -8.13(m, 4H), 8.44-8.83(s, 1H), 9.45-10.14(br.s., 2H). [M+H] _calcd for _{C16H16N5Cl 314} ; found 314.

Example 18: 4-[5-(4-Fluorophenyl)-2-{[(3S)-pyrrolidin-3-ylmethyl]amino}pyrimidin-4-yl]benzonitrile

(3R)-3-({[5-Chloro-4-(4-cyanophenyl)pyrimidin-2-yl]amino}methyl)pyrrolidine-1-carboxylate was used according to the procedure used to prepare Example 16 tert-Butyl acid and (4-fluorophenyl)boronic acid prepared the TFA salt of the title compound in 34% yield. ¹ H NMR (400 MHz, DMSO-d ₆ ): δppm 1.59-1.85 (m, 1H), 1.97-2.17 (m, 1H), 2.59-2.72 (m, 1H), 2.82-3.01 (m, 1H), 3.06 -3.36(m, 2H), 3.37-3.50(m, 2H), 7.15(d, J=7.07Hz, 4H), 7.40-7.56(m, 2H), 7.67-7.79(m, 1H), 7.79-7.88 (m, 2H), 8.38 (s, 1H), 8.54-8.78 (m, 2H). [ _M +H] _calcd for _C22H20N5F 374; found 374.

Example 19: 4-[5-(4-Chlorophenyl)-2-{[(3S)-pyrrolidin-3-ylmethyl]amino}pyrimidin-4-yl]benzonitrile

(3R)-3-({[5-Chloro-4-(4-cyanophenyl)pyrimidin-2-yl]amino}methyl)pyrrolidine-1-carboxylate was used according to the procedure used to prepare Example 16 The TFA salt of the title compound was prepared from tert-butyl acid and (4-chlorophenyl)boronic acid, pinacol ester in 31% yield. ¹ H NMR (400MHz, DMSO-d ₆ ): δppm 1.62-1.83(m,1H), 1.94-2.17(m,1H), 2.62-2.74(m,1H), 2.86-3.02(m,1H), 3.13(m,1H),3.27(m,2H),3.43(m,2H),7.07-7.19(m,2H),7.29-7.43(m,2H),7.44-7.56(m,2H),7.62- 7.75(m, 1H), 7.77-7.89(m, 2H), 8.40(s, 1H), 8.60(br.s., 1H). [ _M +H] _calcd for _C22H20N5Cl 390; found 390.

Preparation 20A: (3R)-tert-butyl 3-({[5-chloro-4-(4-cyanophenyl)pyrimidin-2-yl]oxy}methyl)pyrrolidine-1-carboxylate

To a round bottom flask loaded with tert-butyl (3R)-3-(hydroxymethyl)pyrrolidine-1-carboxylate (664 mg, 3.3 mmol) in DMF (10 mL) was added NaH (144 mg) at 0 °C , 3.6 mmol, 60%). The reaction was allowed to stir at ambient temperature for 30 minutes before 4-(2,5-dichloropyrimidin-4-yl)benzonitrile (744 mg, 3 mmol) was added at 0 °C. The reaction was allowed to warm to ambient temperature and stirring was continued for 16 hours. The reaction was quenched with saturated _NH4Cl and taken up in EtOAc. The organic layer was washed sequentially with water (3X) and brine, dried _{over Na2SO4} , and concentrated in vacuo. The residue was purified by column chromatography (0-40% gradient of EtOAc in hexanes) to afford the title compound (655 mg, 53%) as a yellow amorphous solid. [ _{M +} H] _calcd for _C21H23N4O3Cl 415; found 415.

Example 20: 4-[5-(4-Methylphenyl)-2-[(3R)-pyrrolidin-3-ylmethoxy]pyrimidin-4-yl]benzonitrile

To the loaded (3R)-3-({[5-chloro-4-(4-cyanophenyl)pyrimidin-2-yl]oxy}methyl)pyrrolidine in dioxane (3 mL) -1-Carboxylic acid tert-butyl ester (103 mg, 0.25 mmol) was added with (4-methylphenyl)boronic acid (68 mg, 0.5 mmol), PdCl ₂ (dppf) (36 mg, 0.05 mmol) and Na ₂ CO ₃ (1 mL, 2M). The mixture was purged with N2 for ₂ minutes and sealed. The reaction was irradiated in the microwave at 120°C for 2 hours. Water was added and the mixture was extracted with EtOAc (3X). The combined organic layers _were dried over _Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (0-40% gradient of EtOAc in hexanes) to afford a yellow amorphous foam which was purified by prep-HPLC (ACN in water and 0.1% _HCO2H ) 75%-95% gradient) for further purification to afford (3R)-3-({[4-(4-cyanophenyl)-5-(4-methylphenyl)pyrimidine as a yellow amorphous foam -2-yl]oxy}methyl)pyrrolidine-1-carboxylate tert-butyl ester. The foam was dissolved in DCM (2 mL) and then TFA (2 mL) was added dropwise. The reaction was stirred at ambient temperature for 30 minutes and concentrated in vacuo to afford the TFA salt of the title compound as an off-white amorphous foam (35 mg, 30%). ¹ H NMR (400MHz, DMSO-d ₆ ): δppm 1.70-1.96(m,1H), 2.05-2.23(m,1H), 2.31(s,3H), 2.76-2.91(m,1H), 3.00-3.13 (m,1H),3.13-3.24(m,1H),3.25-3.35(m,1H),3.35-3.48(m,1H),4.34-4.52(m,2H),7.01-7.13(m,2H) ,7.18(d,J＝8.08Hz,2H),7.55(d,J＝8.34Hz,2H),7.83(d,J＝8.34Hz,2H),8.67(s,1H),8.69-8.87(m, 2H). [M ₊ H] _calcd for _C23H22N4O 371; found 371.

Preparation 21A: (3aR,6aS)-5-[5-Chloro-4-(4-cyanophenyl)pyrimidin-2-yl]-octahydropyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester

To a vial containing 4-(2,5-dichloropyrimidin-4-yl)benzonitrile (144 mg, 0.58 mmol) in ethanol (2 mL) was added (3aR,6aS)-octahydropyrrolo[3,4 -c] tert-butyl pyrrole-2-carboxylate (123 mg, 0.58 mmol) and DIEA (144 [mu]L, 1.2 mmol). The reaction was stirred at 100°C for 1 hour. The reaction was concentrated in vacuo and the residue was purified by column chromatography (0-50% gradient of EtOAc in hexanes) to afford the title compound (242 mg, 98%) as a yellow amorphous solid. [ _{M +} H] _calcd for _C22H24N5O2Cl 426; found 426.

Example 21: 4-{2-[(3aR,6aS)-Octahydropyrrolo[3,4-c]pyrrol-2-yl]-5-(4-methylphenyl)pyrimidin-4-yl} benzonitrile

(3aR,6aS)-5-[5-chloro-4-(4-cyanophenyl)pyrimidin-2-yl]-octahydropyrrolo[3,4-b was used according to the procedure used to prepare Example 16 ] tert-butyl pyrrole-2-carboxylate and (4-methylphenyl)boronic acid to prepare the title compound as a TFA salt in 33% yield. ¹ H NMR (400MHz, DMSO-d ₆ ): δppm 2.29(s, 3H), 2.98-3.27(m, 4H), 3.46(m, 2H), 3.60-3.70(m, 2H), 3.72-3.83(m ,2H),7.01(d,J＝8.08Hz,2H),7.13(d,J＝7.83Hz,2H),7.52(d,J＝8.34Hz,2H),7.81(d,J＝8.08Hz,2H) ), 8.44(s, 1H), 8.78-8.98(m, 2H). [ _M +H] calcd for _{C24H23N5 382} ; found 382.

Example 22: 4-[5-(4-Methylphenyl)-2-{octahydro-1H-pyrrolo[3,4-c]pyridin-5-yl}pyrimidin-4-yl]benzonitrile

The TFA salt of the title compound was prepared in 37% yield according to the procedure used to prepare Example 21 starting from tert-butyl octahydro-lH-pyrrolo[3,4-c]pyridine-2-carboxylate. ¹ H NMR (400 MHz, methanol-d ₄ ): δppm 1.53-1.70 (m, 1H), 1.84-1.99 (m, 1H), 2.32 (s, 3H), 2.59-2.75 (m, 2H), 2.99-3.11 (m,1H), 3.18-3.28(m,1H), 3.37-3.48(m,3H), 3.68-3.82(m,1H), 4.41-4.61(m,2H), 6.94-7.06(d,J= 8.08Hz, 2H), 7.13(d, J＝8.08Hz, 2H), 7.54-7.59(d, J＝8.08Hz, 2H), 7.63(d, J＝8.08Hz, 3H), 8.38(s, 1H) . [M+H] _calcd for _{C25H25N5 396} ; found 396.

Example 23: 4-{2-[(3aR,8aS)-Decahydropyrrolo[3,4-d]azepin-6-yl]-5-(4-methylphenyl)pyrimidine-4- base}benzonitrile

The title compound was prepared in 28% yield according to the procedure used to prepare Example 21 starting from (3aR,8aS)-decahydropyrrolo[3,4-d]azepine-2-carboxylate tert-butyl ester TFA salt. ¹ H NMR (400 MHz, DMSO-d ₆ ): δppm 1.62-1.79 (m, 2H), 1.82-1.99 (m, 2H), 2.29 (s, 3H), 2.55-2.65 (m, 2H), 2.76-2.95 (m, 2H), 3.28-3.40 (m, 2H), 3.40-3.54 (m, 2H), 4.25-4.43 (m, 2H), 7.00 (d, J=8.08Hz, 2H), 7.13 (d, J ＝7.83Hz, 2H), 7.51(d, J＝8.59Hz, 2H), 7.80(d, J＝8.59Hz, 2H), 8.43(s, 1H), 8.53-8.64(m, 1H), 8.64-8.79 (m, 1H). [M+H] _calcd for _{C26H27N5 410} ; found 410.

Example 24: 4-{2-[(3aR,8aS)-Decahydropyrrolo[3,4-d]azepin-6-yl]-5-(4-fluorophenyl)pyrimidin-4-yl }benzonitrile

(3aR,8aS)-6-[5-chloro-4-(4-cyanophenyl)pyrimidin-2-yl]-decahydropyrrolo[3,4-d was used according to the procedure used to prepare Example 21 ] tert-butyl azepine-2-carboxylate and (4-fluorophenyl)boronic acid The title compound was prepared as a TFA salt in 32% yield. ¹ H NMR (400 MHz, DMSO-d ₆ ): δppm 1.62-1.79 (m, 2H), 1.82-1.99 (m, 2H), 2.50-2.62 (m, 2H), 2.77-2.93 (m, 2H), 3.30 -3.42(m, 2H), 3.42-3.55(m, 2H), 4.26-4.42(m, 2H), 7.14-7.20(m, 4H), 7.50(d, J=8.34Hz, 2H), 7.81(d , J=8.34Hz, 2H), 8.40-8.52 (m, 1H), 8.52-8.64 (m, 1H), 8.67-8.79 (m, 1H). [ _M +H] _calcd for _C25H24N5F 414; found 414.

Example 25: 4-(2-{[(3S)-pyrrolidin-3-ylmethyl]amino}-5-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl)benzonitrile

(3R)-3-({[5-Chloro-4-(4-cyanophenyl)pyrimidin-2-yl]amino}methyl)pyrrolidine-1-carboxylic acid was used according to the procedure used to prepare Example 16 tert-Butyl ester prepared the TFA salt of the title compound in 46% yield. ¹ H NMR (400MHz, DMSO-d ₆ ): δppm 1.65-1.81 (m, 1H), 2.00-2.14 (m, 1H), 2.59-2.73 (m, 1H), 2.89-2.99 (m, 1H), 3.09 -3.20(m,1H),3.21-3.37(m,2H),3.38-3.50(m,2H),7.35(d,J=8.08Hz,2H),7.44-7.57(m,2H),7.67(d , J=8.08Hz, 2H), 7.80 (d, J=8.34Hz, 2H), 8.46 (s, 1H), 8.65 (br.s., 2H). _{[ M} +H] _calcd for _C23H20N5F3 424; found 424.

Example 26: 4-[5-(2-Cyclopropylethynyl)-2-{[(3S)-pyrrolidin-3-ylmethyl]amino}pyrimidin-4-yl]benzonitrile

To the compound loaded with (3R)-3-({[5-chloro-4-(4-cyanophenyl)pyrimidin-2-yl]amino}methyl)pyrrolidine-1-carboxyl in ACN (3 mL) To a vial of tert-butyl acid (103 mg, 0.25 mmol) was added cyclopropane acetylene (33 mg, 0.5 mmol), PdCl ₂ (ACN) ₂ (2.6 mg, 0.01 mmol), XPhos (4 mg, 0.02 mmol) and K ₂ CO ₃ ( 103 mg, 0.75 mmol). The mixture was purged with N2 for ₂ minutes and sealed. The reaction was kept at 100°C for 16 hours. Water was added and the mixture was extracted with EtOAc (3X). The combined organic layers _were dried over _Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (0-50% gradient of EtOAc in hexanes) to afford a yellow amorphous residue. The residue was dissolved in DCM (2 mL) followed by dropwise addition of TFA (2 mL). The reaction was stirred at ambient temperature for 30 minutes and concentrated in vacuo. The residue was further purified by prep-HPLC (5%-95% gradient of ACN in water and 0.1% _HCO2H ) to afford the formate salt of the title compound as a yellow amorphous foam (3 mg, 3%). ¹ H NMR (400 MHz, CD ₃ OD): δppm 0.58-0.75 (m, 2H), 0.80-0.96 (m, 2H), 1.36-1.53 (m, 1H), 1.72-1.93 (m, 1H), 2.10- 2.31(m, 1H), 2.66-2.82(m, 1H), 2.95-3.09(m, 1H), 3.51-3.62(m, 5H), 7.76-7.90(m, 2H), 8.14-8.27(m, 2H ), 8.34-8.45 (m, 1H). [M+H] _calcd for _{C21H21N5 344} ; found 344.

Example 27: 4-(2-{[(3aR,5S,6aS)-octahydrocyclopentadieno[c]pyrrol-5-yl]amino}-5-(4-methylphenyl)pyrimidine- 4-yl)benzonitrile

To (3aR,5S,6aS)-5-{[5-chloro-4-(4-cyanophenyl)pyrimidine-2-according to the procedure used to prepare 16B, contained in dioxane (3 mL) (4-methylphenyl)boronic acid (155.0 mg, 1.14 mmol), Pd (dppf)Cl2 (80.0 _mg , 0.11 mmol) and _Na2CO3 ( ₁ mL, 2M). The mixture was purged with N2 for ₂ minutes and sealed. The reaction mixture was irradiated in a microwave at 130°C for 4 hours. Water was added and the mixture was extracted with EtOAc (3X). The combined organic layers _were dried over _Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (petroleum ether:ethyl acetate=5:1) to provide a crude residue. HCl (5 mL, 4M in dioxane) was added and stirring was continued at 30°C for 1 hour. The mixture was concentrated in vacuo and purified by preparative HPLC to afford the title compound as a pale yellow foam (40.0 mg, 33.7% yield). ¹ HNMR (methanol-d ₄ , 400MHz): δ 1.87-1.84(m, 4H), 2.32(s, 3H), 2.63-2.59(m, 2H), 2.80-2.70(m, 2H), 3.12-3.07 (m,2H),4.47-4.40(m,1H),6.98(d,J=8.0Hz,2H),7.12(d,J=8.0Hz,2H),7.54(d,J=8.4Hz,2H) , 7.62 (d, J=8.4 Hz, 2H), 8.29 (s, 1H). [M+H] _calcd for _{C25H25N5 396} ; found 396.

Example 28: (±)-4-(2-{[(3-Fluoropyrrolidin-3-yl)methyl]amino}-5-(4-methylphenyl)pyrimidin-4-yl)benzyl Nitrile

(±)-3-({[5-chloro-4-(4-cyanophenyl)pyrimidin-2-yl]amino}methyl)-3-fluoropyrrolidine was used according to the procedure used to prepare Example 27 - tert-Butyl 1-carboxylate and (4-methylphenyl)boronic acid The title compound was prepared in 29% yield. ¹ H NMR (methanol-d ₄ , 400MHz): δ 2.00-2.15 (m, 2H), 2.34 (s, 3H), 3.17-2.96 (m, 4H), 3.95 (d, J=19.2Hz, 2H) ,7.02(d,J＝8.8Hz,2H),7.14(d,J＝8.8Hz,2H),7.57(d,J＝8.8Hz,2H),7.65(d,J＝8.8Hz,2H),8.35 (s, 1H). [M+H] _calcd for _{C23H22N5F 388} ; found 388.

Example 29: (±)-4-[5-(4-methylphenyl)-2-[(piperidin-3-yl)amino]pyrimidin-4-yl]benzonitrile

3-{[5-Chloro-4-(4-cyanophenyl)pyrimidin-2-yl]amino}piperidine-1-carboxylate tert-butyl ester and (4- methylphenyl)boronic acid to prepare the title compound in 29% yield. ¹ H NMR (CDCl ₃ , 400MHz): δ 8.34 (s, 1H), 7.56-7.50 (m, 4H), 7.11 (d, J=8.0Hz, 2H), 6.97 (d, J=8.0Hz, 2H) ),5.53-5.51(m,1H),4.11-4.07(m,1H),3.31-3.27(m,1H),2.95-2.85(m,1H),2.79-2.67(m,2H),2.36(s , 3H), 2.05-1.95 (m, 1H), 1.83-1.79 (m, 2H), 1.70-1.60 (m, 2H). [M+H] _calcd for _{C23H23N5 370} ; found 370.

Example 30: 4-[5-(4-Methylphenyl)-2-[(piperidin-4-yl)amino]pyrimidin-4-yl]benzonitrile

4-{[5-Chloro-4-(4-cyanophenyl)pyrimidin-2-yl]amino}piperidine-1-carboxylate tert-butyl ester and (4- methylphenyl)boronic acid to prepare the title compound in 17% yield. ¹ H NMR (methanol-d ₄ , 400 MHz): δ 8.31 (s, 1H), 7.64 (d, J=8.4 Hz, 2H), 7.55 (d, J=8.4 Hz, 2H), 7.13 (d, J ＝8.0Hz, 2H), 7.05(d, J＝8.0Hz, 2H), 4.03-4.01(m, 1H), 3.14-3.10(m, 2H), 2.77-2.71(m, 2H), 2.34(s, 3H), 2.10-2.07 (m, 2H), 1.58-1.52 (m, 2H). [M+H] _calcd for _{C23H23N5 370} ; found 370.

Example 31: (±)-4-[5-(4-methylphenyl)-2-[(piperidin-3-ylmethyl)amino]pyrimidin-4-yl]benzonitrile

(±)-3-({[5-chloro-4-(4-cyanophenyl)pyrimidin-2-yl]amino}methyl)piperidine-1-carboxylate was used according to the procedure used to prepare Example 27 The title compound was prepared from tert-butyl acid and (4-methylphenyl)boronic acid in 18% yield. ¹ H NMR (methanol-d ₄ , 400MHz): δ 8.29(s, 1H), 7.63(d, J=8.4Hz, 2H), 7.55(d, J=8.4Hz, 2H), 7.12(d, J= 8.0Hz, 2H), 6.99(d, J=8.0Hz, 2H), 3.35-3.31(m, 2H), 3.14-3.11(m, 1H), 3.00-2.97(m, 1H), 2.57-2.56(m , 1H), 2.40-2.32 (m, 4H), 1.93-1.91 (m, 2H), 1.75-1.72 (m, 1H), 1.54-1.47 (m, 2H). [ _M +H] calcd for _{C24H25N5 384} ; found 384.

Example 32: 4-[5-(4-Methylphenyl)-2-[(piperidin-4-ylmethyl)amino]pyrimidin-4-yl]benzonitrile

4-({[5-Chloro-4-(4-cyanophenyl)pyrimidin-2-yl]amino}methyl)piperidine-1-carboxylate tert-butyl ester was used according to the procedure used to prepare Example 27 and (4-methylphenyl)boronic acid to prepare the title compound in 35% yield. ¹ H NMR (methanol-d ₄ , 400 MHz): δ 8.29 (s, 1H), 7.64 (d, J=8.0 Hz, 2H), 7.56 (d, J=8.0 Hz, 2H), 7.13 (d, J =8.0Hz,2H),7.00(d,J=8.0Hz,2H),3.39-3.36(m,2H),3.09-3.05(m,2H),2.63-2.59(m,2H),2.34(s, 3H), 1.83-1.79 (m, 3H), 1.31-1.23 (m, 2H). [ _M +H] calcd for _{C24H25N5 384} ; found 384.

Example 33: (±)-4-[5-(4-methylphenyl)-2-[(morpholin-2-ylmethyl)amino]pyrimidin-4-yl]benzonitrile

(±)-2-({[5-chloro-4-(4-cyanophenyl)pyrimidin-2-yl]amino}methyl)morpholine-4-carboxylate was used according to the procedure used to prepare Example 21 tert-Butyl acid and (4-methylphenyl)boronic acid prepared the TFA salt of the title compound in 19% yield. ¹ H NMR (400MHz, DMSO-d ₆ ): δppm 2.28(s,3H), 2.75-2.91(m,1H), 2.92-3.09(m,1H), 3.10-3.17(m,1H), 3.24-3.34 (m,1H),3.36-3.59(m,2H),3.62-3.77(m,1H),3.86-3.94(m,1H),3.94-4.02(m,1H),7.00(d,J=8.08Hz ,2H),7.12(d,J＝7.83Hz,2H),7.42-7.53(m,2H),7.55-7.65(m,1H),7.80(d,J＝8.08Hz,2H),8.37(s, 1H), 8.64-8.94 (m, 2H). [M+H] _calcd for _{C22H22N5O 386} ; found 386.

Example 34: (±)-4-[5-(4-Fluorophenyl)-2-[(morpholin-2-ylmethyl)amino]pyrimidin-4-yl]benzonitrile

(±)-2-({[5-chloro-4-(4-cyanophenyl)pyrimidin-2-yl]amino}methyl)morpholine-4-carboxylate was used according to the procedure used to prepare Example 21 tert-Butyl acid and (4-fluorophenyl)boronic acid prepared the TFA salt of the title compound in 44% yield. ¹ HNMR (400MHz, DMSO-d ₆ ): δppm 3.59(m, 2H), 3.61-3.77(m, 1H), 3.84-3.95(m, 1H), 3.96-4.00(m, 1H), 7.16(d, J=7.07Hz, 4H), 7.40-7.59( m, 2H), 7.60-7.74 (m, 1H), 7.81 (d, J=8.34 Hz, 2H), 8.40 (s, 1H), 8.65-8.98 (m, 2H). [ _M +H] calculated for _{C22H20N5OF 390} ; found 390.

Example 35: 4-(2-{2,7-Diazaspiro[4.4]non-2-yl}-5-(4-methylphenyl)pyrimidin-4-yl)benzonitrile

The TFA salt of the title compound was prepared in 24% yield according to the procedure used to prepare Example 21 starting with tert-butyl 2,7-diazaspiro[4.4]nonane-2-carboxylate. ¹ H NMR (400 MHz, DMSO-d ₆ ): δppm 1.88-2.17 (m, 4H), 2.28 (s, 3H), 3.08-3.41 (m, 4H), 3.55-3.63 (m, 1H), 3.63-3.73 (m,3H),7.00(d,J=8.08Hz,2H),7.12(d,J=7.83Hz,2H),7.51(d,J=8.08Hz,2H),7.80(d,J=8.34Hz , 2H), 8.45 (s, 1H), 8.74-9.01 (br.s., 2H). [M+H] _calcd for _{C25H25N5 396} ; found 396.

Example 36: 4-(2-{2,8-Diazaspiro[4.5]dec-2-yl}-5-(4-methylphenyl)pyrimidin-4-yl)benzonitrile

2-[5-Chloro-4-(4-cyanophenyl)pyrimidin-2-yl]-2,8-diazaspiro[4.5]decane-8- tert-Butyl carboxylate and (4-methylphenyl)boronic acid prepared the TFA salt of the title compound in 42% yield. ¹ H NMR (400MHz, DMSO-d ₆ ): δppm 1.65-1.82 (m, 4H), 1.90-1.99 (m, 2H), 2.28 (m, 3H), 3.13 (br.s., 4H), 3.52 ( s, 2H), 3.66(t, J＝6.95Hz, 2H), 7.00(s, 2H), 7.12(d, J＝7.83Hz, 2H), 7.52(d, J＝8.34Hz, 2H), 7.80( d, J=8.59Hz, 2H), 8.29-8.54 (m, 3H). [M+H] _calcd for _{C26H27N5 410} ; found 410.

Example 37: 4-[5-(4-Methylphenyl)-2-{octahydro-1H-pyrrolo[3,4-c]pyridin-2-yl}pyrimidin-4-yl]benzonitrile

2-[5-Chloro-4-(4-cyanophenyl)pyrimidin-2-yl]-octahydro-1H-pyrrolo[3,4-c]pyridine- tert-Butyl 5-carboxylate and (4-methylphenyl)boronic acid prepared the TFA salt of the title compound in 42% yield. ¹ H NMR (400 MHz, DMSO-d ₆ ): δppm 1.60-1.79 (m, 1H), 1.84-2.01 (m, 1H), 2.28 (s, 3H), 2.50-2.62 (m, 2H), 2.96-3.20 (m,3H),3.20-3.35(m,1H),3.53-3.76(m,4H),7.01(d,J=8.08Hz,2H),7.13(d,J=7.83Hz,2H),7.52( d, J=8.34Hz, 2H), 7.80 (d, J=8.34Hz, 2H), 8.42 (s, 1H), 8.47-8.69 (m, 1H). [M+H] _calcd for _{C25H25N5 396} ; found 396.

Example 38: 4-[5-(4-Methylphenyl)-2-{octahydro-1H-pyrrolo[3,2-c]pyridin-5-yl}pyrimidin-4-yl]benzonitrile

The TFA salt of the title compound was prepared in 48% yield according to the procedure used to prepare Example 21 starting with tert-butyl octahydro-lH-pyrrolo[3,2-c]pyridine-l-carboxylate. ¹ H NMR (400 MHz, methanol-d ₄ ): δppm 1.77-2.00 (m, 2H), 2.05-2.23 (m, 2H), 2.32 (s, 3H), 2.56-2.69 (m, 1H), 3.42-3.55 (m,3H),3.79-3.88(m,1H),3.90-4.02(m,1H),4.30-4.40(m,1H),4.40-4.52(m,1H),6.99(d,J=8.08Hz ,2H),7.13(d,J＝7.83Hz,2H),7.52-7.59(d,J＝8.14Hz,2H),7.63(d,J＝8.34Hz,2H),8.34-8.44(m,1H) . [M+H] _calcd for _{C25H25N5 396} ; found 396.

Example 39: 4-(2-{2,8-Diazaspiro[4.5]dec-8-yl}-5-(4-methylphenyl)pyrimidin-4-yl)benzonitrile

The TFA salt of the title compound was prepared in 62% yield according to the procedure used to prepare Example 21 starting with tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate. ¹ H NMR (400 MHz, DMSO-d ₆ ): δppm 1.50-1.71 (m, 4H), 1.84-1.94 (m, 2H), 2.28 (s, 3H), 3.02-3.11 (m, 2H), 3.23-3.38 (m,2H),3.73-3.95(m,4H),7.01(d,J=8.08Hz,2H),7.13(d,J=8.08Hz,2H),7.51(d,J=8.34Hz,2H) , 7.80(d, J=8.34Hz, 2H), 8.43(s, 1H), 8.84(br.s., 2H). [M+H] _calcd for _{C26H27N5 410} ; found 410.

Example 40: 4-(2-{1,8-Diazaspiro[4.5]dec-8-yl}-5-(4-methylphenyl)pyrimidin-4-yl)benzonitrile

The TFA salt of the title compound was prepared in 64% yield according to the procedure used to prepare Example 21 starting with tert-butyl 1,8-diazaspiro[4.5]decane-1-carboxylate. ¹ H NMR (400 MHz, DMSO-d ₆ ): δppm 1.77-1.92 (m, 4H), 1.93-2.08 (m, 4H), 2.29 (s, 3H), 3.20-3.35 (m, 2H), 3.45-3.58 (m, 2H), 4.27-4.41 (m, 2H), 7.02 (d, J=7.83Hz, 2H), 7.13 (d, J=7.83Hz, 2H), 7.52 (d, J=8.34Hz, 2H) , 7.81(d, J=8.34Hz, 2H), 8.46(s, 1H) 8.64-8.79(m, 1H). [M+H] _calcd for _{C26H27N5 410} ; found 410.

Example 41: 4-[5-(4-Methylphenyl)-2-{9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}pyrimidin-4-yl ] benzonitrile

7-[5-Chloro-4-(4-cyanophenyl)pyrimidin-2-yl]-9-oxa-3,7-diazabicyclo[3.3. 1] tert-Butyl nonane-3-carboxylate and (4-methylphenyl)boronic acid The title compound was prepared as the HCl salt in 26% yield. ¹ H NMR (400MHz, DMSO-d ₆ ): δppm 2.30(s, 3H), 3.27-3.44(m, 4H), 3.44-3.55(m, 1H), 3.62-3.75(m, 1H), 4.27( m, 2H), 4.25-4.33 (m, 4H), 4.57 (d, J=13.39Hz, 2H), 7.04 (d, J=8.08Hz, 2H), 7.17 (d, J=7.83Hz, 2H), 7.56(d,J＝8.59Hz,2H),7.83(d,J＝8.59Hz,2H),8.13-8.38(m,1H),8.52-8.64(m,1H),9.43(br.s.,1H) ). [ _M +H] calcd for _{C24H23N5O 398} ; found 398.

Example 42: 4-[5-(4-Fluorophenyl)-2-{9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}pyrimidin-4-yl] benzonitrile

7-[5-Chloro-4-(4-cyanophenyl)pyrimidin-2-yl]-9-oxa-3,7-diazabicyclo[3.3. 1] tert-Butyl nonane-3-carboxylate and (4-fluorophenyl)boronic acid The title compound was prepared as the HCl salt in 20% yield. ¹ H NMR (400MHz, DMSO-d ₆ ): δppm 3.25-3.44 (m, 4H), 3.44-3.53 (m, 2H), 3.66-3.69 (m, 2H), 4.28 (br.s., 2H) ,4.57(d,J＝13.39Hz,2H),7.17-7.25(m,4H),7.54(d,J＝8.59Hz,2H),7.85(d,J＝8.59Hz,2H),8.13-8.31( m, 1H), 8.60 (s, 1H), 9.20-9.41 (m, 1H). [ _M +H] calculated for _{C23H20N5OF 402} ; found 402.

Preparation 43A: Methyl 1-(4-cyanophenyl)-5-(4-methylphenyl)pyrazole-3-carboxylate

Mix 4-(4-methylphenyl)-2,4-dioxobutyric acid methyl ester (1.0 g, 4.55 mmol) and 4-hydrazinobenzonitrile (0.85 g, 5.0 mmol) in AcOH (20 mL) The mixture was stirred at 118 °C for 16 hours. The solvent was removed in vacuo and the residue was purified by column chromatography (0-80%, EtOAc:PE) to give 1.3 g (90%) of the title compound as a yellow solid. ¹ H NMR (CDCl ₃ , 400MHz): δ 7.65 (d, J=8.0 Hz, 2H), 7.48 (d, J=8.0 Hz, 2H), 7.18 (d, J=8.0 Hz, 2H), 7.10 ( d, J=8.0Hz, 2H), 7.02 (s, 1H), 3.99 (s, 3H), 2.39 (s, 3H). [ _{M +} H] _calcd for _C19H15N3O2 318; found 318.

Preparation 43B: 1-(4-Cyanophenyl)-5-(4-methylphenyl)pyrazole-3-carboxylic acid

Methyl 1-(4-cyanophenyl)-5-(4-methylphenyl)pyrazole-3-carboxylate (1.3 g, 4.1 mmol) and LiOH (0.3 g, 12.3 mmol) in MeOH/ The mixture in _H2O (20 mL/20 mL) was stirred at room temperature for 3 hours. The MeOH was removed in vacuo and _H2O (20 mL) was added. The pH of the solution was adjusted to 4 using HCl (0.6M) solution. The mixture was extracted with DCM (80 mL×3), washed with brine (50 mL×2) and dried over Na ₂ SO ₄ . The solvent was evaporated in vacuo to give 1.1 g (88%) of the title compound as a yellow solid. ¹ H NMR (methanol-d4, 400MHz): δ 7.78 (d, J=8.4Hz, 2H), 7.52 (d, J=8.8Hz, 2H), 7.21 (d, J=8.0Hz, 2H), 7.15 (d, J=8.0 Hz, 2H), 7.02 (s, 1H), 2.35 (s, 3H). [ _{M +} H] _calcd for _C18H13N3O2 304; found 304.

Preparation 43C: tert-butyl N-[1-(4-cyanophenyl)-5-(4-methylphenyl)pyrazol-3-yl]carbamate

1-(4-Cyanophenyl)-5-(4-methylphenyl)pyrazole-3-carboxylic acid (1.1 g, 3.63 mmol), DPPA (1.2 g, 4.36 mmol) and TEA (0.44 g) were combined , 4.36 mmol) in dioxane/t-BuOH (20 mL/20 mL) was stirred at 110 °C for 16 h. The solvent was removed in vacuo and the crude residue was purified by column chromatography (0-50%, EtOAc:PE) to give 0.3 g (22%) of the title compound as a yellow solid. ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.58-7.56 (d, J=8.0 Hz, 2H), 7.36-7.34 (d, J=8.0 Hz, 2H), 7.18-7.13 (m, 5H), 6.81 (br.S., 1H), 2.38 (s, 3H), 1.54 (s, 9H). [M ₊ H] _calcd for _C22H22N4O2 375 _; found 375.

Preparation 43D: 3-[[[1-(4-Cyanophenyl)-5-(4-methylphenyl)pyrazol-3-yl]-[(2-methylpropan-2-yl)oxy Carbonyl]amino]methyl]pyrrolidine-1-carboxylate tert-butyl ester

N-[1-(4-cyanophenyl)-5-(4-methylphenyl)pyrazol-3-yl]carbamic acid tert-butyl ester (80 mg, 0.21 mmol), 3-[(4- A mixture of methylphenyl)sulfonyloxymethyl]pyrrolidine-1-carboxylate tert-butyl ester (92 mg, 0.25 mmol) and _{Cs2CO3 (} 210 mg, 0.64 mmol) in DMF (6 mL) at 90 °C Lower reflux continued for 16 hours. The mixture was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL x ₂ ) and dried over _Na2SO4 . The solvent was removed in vacuo and the crude residue was purified by preparative HPLC to give 76 mg (63%) of the title compound as a yellow oil. ¹ H NMR (CDCl ₃ , 400MHz): δ 7.57 (d, J=8.4Hz, 2H), 7.37 (d, J=8.4Hz, 2H), 7.19-7.12 (m, 4H), 6.80 (brs, 1H) ), 4.05-3.95(m, 2H), 3.51(m, 2H), 3.38-3.26(m, 1H), 3.17(dd, J ₁ =8.0Hz, J ₂ =12.0Hz, 1H), 2.75(m, 1H), 2.39(s, 3H), 2.03-1.93(m, 1H), 1.78-1.68(m, 1H), 1.57(s, 9H), 1.45(s, 9H). [M ₊ H] _calcd for _{C32H39N5O4 558} ; found 558.

Example 43: 4-[5-(4-Methylphenyl)-3-(pyrrolidin-3-ylmethylamino)pyrazol-1-yl]benzonitrile

to 3-[[[1-(4-cyanophenyl)-5-(4-methylphenyl)pyrazol-3-yl]-[(2-methylpropan-2-yl)oxycarbonyl] Amino]methyl]pyrrolidine-1-carboxylate tert-butyl ester (76 mg, 0.09 mmol) in DCM (2 mL) was added dropwise HCl/dioxane (4M, 5mL). The mixture was stirred at room temperature for 2 hours and concentrated in vacuo. The crude residue was purified by preparative HPLC to give 24 mg (39%) of the title compound as a yellow oil. ¹ HNMR (methanol-d4, 400MHz): δ 8.53 (brs, 1H), 7.63 (d, J=8.0Hz, 2H), 7.35 (d, J=8.0Hz, 2H), 7.20 (d, J=8.0 Hz, 2H), 7.13(d, J=8.0Hz, 2H), 5.94(s, 1H), 3.46-3.38(m, 2H), 3.38-3.32(m, 2H), 3.30-3.25(m, 1H) , 3.12 (dd, J ₁ =8.0 Hz, J ₂ =12.0 Hz, 1H), 2.78 (m, 1H), 2.36 (s, 3H), 2.27-2.17 (m, 1H), 1.86 (m, 1H). [M+H] _calcd for _{C22H23N5 358} ; found 358.

Preparation 44A: (3S)-3-[[[1-(4-cyanophenyl)-5-(4-methylphenyl)pyrazol-3-yl]-[(2-methylpropan-2 -yl)oxycarbonyl]amino]methyl]pyrrolidine-1-carboxylate tert-butyl ester

According to the procedure used to prepare 43D from tert-butyl N-[1-(4-cyanophenyl)-5-(4-methylphenyl)pyrazol-3-yl]carbamate and (3S)-3 -[(4-Methylphenyl)sulfonyloxymethyl]pyrrolidine-1-carboxylate tert-butyl ester The title compound was prepared in 34% yield. ¹ H NMR(CDCl ₃ , 400MHz)δ7.57(d,J=8.4Hz,2H),7.37(d,J=8.4Hz,2H),7.21-7.09(m,4H),6.82(br.s. ,1H),4.07-3.91(m,2H),3.58-3.41(m,2H),3.32(m,1H),3.16(br.s.,1H),2.75(m,1H),2.38(s, 3H), 1.98 (m, 1H), 1.73 (m, 1H), 1.60-1.53 (s, 9H), 1.45 (s, 9H). [M ₊ H] _calcd for _{C32H39N5O4 558} ; found 558.

Example 44: 4-[5-(4-Methylphenyl)-3-[[(3S)-pyrrolidin-3-yl]methylamino]pyrazol-1-yl]benzonitrile

(3S)-3-[[[1-(4-cyanophenyl)-5-(4-methylphenyl)pyrazol-3-yl]-[( The title compound was prepared in 59% yield starting from tert-butyl 2-methylprop-2-yl)oxycarbonyl]amino]methyl]pyrrolidine-1-carboxylate. ¹ H NMR (methanol-d4, 400MHz): δ 7.80-7.74 (m, 2H), 7.51-7.45 (m, 2H), 7.26-7.17 (m, 4H), 3.52 (dd, J ₁ =8.0Hz, J ₂ =12.0Hz,1H),3.48-3.40(m,3H),3.35-3.27(m,1H),3.12(dd,J ₁ =8.0Hz,J ₂ =12.0Hz,1H),2.84-2.76( m, 1H), 2.36 (s, 3H), 2.33-2.23 (m, 1H), 1.87-1.84 (m, 1H). [M+H] _calcd for _{C22H23N5 358} ; found 358.

Preparation 45A: (3R)-3-[[[1-(4-cyanophenyl)-5-(4-methylphenyl)pyrazol-3-yl]-[(2-methylpropan-2 -yl)oxycarbonyl]amino]methyl]pyrrolidine-1-carboxylate tert-butyl ester

According to the procedure used to prepare 43D from tert-butyl N-[1-(4-cyanophenyl)-5-(4-methylphenyl)pyrazol-3-yl]carbamate and (3R)-3 -[(4-methylphenyl)sulfonyloxymethyl]pyrrolidine-1-carboxylate tert-butyl ester The title compound was prepared in 40% yield. ¹ H NMR (CDCl ₃ , 400MHz): δ 7.57 (d, J=8.0Hz, 2H), 7.37 (J=8.0Hz, 2H), 7.21-7.09 (m, 4H), 6.82 (br.s, 1H) ),4.08-3.90(m,2H),3.58-3.41(m,2H),3.34-3.30(m,1H),3.17(br.s,1H),2.75(m,1H),2.39(s,3H ), 2.04-1.93(m, 1H), 1.73(m, 1H), 1.53-1.61(s, 9H), 1.45(s, 9H). [M ₊ H] _calcd for _{C32H39N5O4 558} ; found 558.

Example 45: 4-[5-(4-Methylphenyl)-3-[[(3R)-pyrrolidin-3-yl]methylamino]pyrazol-1-yl]benzonitrile

(3R)-3-[[[1-(4-cyanophenyl)-5-(4-methylphenyl)pyrazol-3-yl]-[( The title compound was prepared in 33% yield starting from tert-butyl 2-methylprop-2-yl)-yl)oxycarbonyl]amino]methyl]pyrrolidine-1-carboxylate. ¹ H NMR (methanol-d4, 400MHz): δ7.79-7.70 (d, J=8.4Hz, 2H), 7.46 (d, J=8.4Hz, 2H), 7.26-7.15 (m, 4H), 3.51 ( m, 1H), 3.47-3.39(m, 3H), 3.34-3.30(m, 1H), 3.12(m, 1H), 2.86-2.75(m, 1H), 2.36(s, 3H), 2.32-2.22( m, 1H), 1.87 (m, 1H). [M+H] _calcd for _{C22H23N5 358} ; found 358.

Preparation 46A: 4-[[[1-(4-Cyanophenyl)-5-(4-methylphenyl)pyrazol-3-yl]-[(2-methylpropan-2-yl)oxy Carbonyl]amino]methyl]carboxylate tert-butyl ester

N-[1-(4-cyanophenyl)-5-(4-methylphenyl)pyrazol-3-yl]carbamic acid tert-butyl ester (80 mg, 0.21 mmol), 4-[(4- A mixture of methylphenyl)sulfonyloxymethyl]piperidine-1-carboxylate tert-butyl ester (72 mg, 0.26 mmol) and _{Cs2CO3 (} 210 mg, 0.64 mmol) in DMF (6 mL) at 90 °C Lower reflux continued for 16 hours. The mixture was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL x ₂ ) and dried over _Na2SO4 . The solvent was removed in vacuo and the crude residue was purified by column chromatography (0-33%, EtOAc:PE) to give 82 mg (67%) of the title compound as a yellow solid. ¹ H NMR (CDCl ₃ , 400MHz): δ 7.57 (d, J=8.4Hz, 2H), 7.37 (d, J=8.4Hz, 2H), 7.20-7.12 (m, 4H), 6.80 (br.S .,1H),4.17-4.04(m,2H),3.87(d,J=7.2Hz,2H),2.70(t,J=12.4Hz,2H),2.41(s,3H),2.09-1.98(m , 1H), 1.70 (d, J=12.4Hz, 2H), 1.56 (s, 9H), 1.47 (s, 9H), 1.32-1.19 (m, 2H). [M ₊ H] _calcd for _{C33H41N5O4 572} ; found 572.

Example 46: 4-[5-(4-Methylphenyl)-3-(piperidin-4-ylmethylamino)pyrazol-1-yl]benzonitrile

According to the procedure used to prepare Example 43 from 4-[[[1-(4-cyanophenyl)-5-(4-methylphenyl)pyrazol-3-yl]-[(2-methyl Prop-2-yl)oxycarbonyl]amino]methyl]piperidine-1-carboxylate tert-butyl ester The title compound was prepared as the HCl salt in 57% yield. ¹ H NMR (methanol-d4, 400MHz): δ8.51 (brs, 2H), 7.65 (d, J=8.0 Hz, 2H), 7.36 (d, J=8.0 Hz, 2H), 7.22 (d, J= 8.0Hz, 2H), 7.15(d, J＝8.0Hz, 2H), 5.95(s, 1H), 3.44(d, J＝12.0Hz, 2H), 3.22(d, J＝6.4Hz, 2H), 3.05 -2.98(m, 2H), 2.38(s, 3H), 2.16-1.98(m, 3H), 1.56-1.41(m, 2H). [M+H] _calcd for _{C23H25N5 372} ; found 372.

Preparation 47A: (1S,5R)-6-[[[1-(4-cyanophenyl)-5-(4-methylphenyl)pyrazol-3-yl]-[(2-methylpropane -2-yl)oxycarbonyl]amino]methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate tert-butyl ester

tert-Butyl N-[1-(4-cyanophenyl)-5-(4-methylphenyl)pyrazol-3-yl]carbamate (50.0 mg, 0.133 mmol), (1S,5R) - tert-butyl 6-(chloromethyl)-3-azabicyclo[3.1.0]hexane- ₃ -carboxylate (41.0 mg, 0.14 mmol), _Cs2CO3 (130.0 mg, 0.4 mmol) in DMF The mixture in (6 mL) was refluxed at 90°C for 16 hours. The mixture was extracted with EA (20 mL x 3). The combined organic layers were washed with brine (20 mL x ₂ ) and dried over _Na2SO4 . The solvent was evaporated under vacuum to give the crude product, which was purified by preparative HPLC to give the title compound as a yellow oil (38.0 mg, 50.0%). ¹ H NMR (CDCl ₃ , 400MHz): δ 7.58 (d, J=8.0 Hz, 2H), 7.37 (d, J=8.0 Hz, 2H), 7.19-7.13 (m, 4H), 6.80 (br.s ,1H),3.88(d,J＝6.8Hz,2H),3.62-3.47(m,2H),3.39-3.28(m,2H),2.39(s,3H),1.62(s,2H),1.57( s, 9H), 1.44-1.40 (s, 9H), 1.17 (m, 1H). [M ₊ H] _calcd for _{C33H39N5O4 570} ; found 570.

Example 47: 4-[3-[[(1S,5R)-3-azabicyclo[3.1.0]hex-6-yl]methylamino]-5-(4-methylphenyl)pyrazole -1-yl]benzonitrile

To (1S,5R)-6-[[[1-(4-cyanophenyl)-5-(4-methylphenyl)pyrazol-3-yl]-[(2-methylpropan-2 -yl)oxycarbonyl]amino]methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate tert-butyl ester (38.0 mg, 0.067 mmol) in DCM (5 mL) was added at 0 HCl/dioxane (4M, 10 mL) was added dropwise at °C to -10 °C. The mixture was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo to give the crude product, which was purified by preparative HPLC to give the title compound as a yellow oil (24.0 mg, 38.7%). ¹ H NMR (methanol-d ₄ , 400 MHz): δ 7.72 (d, J=8.0 Hz, 2H), 7.43 (d, J=7.6 Hz, 2H), 7.24-7.14 (m, 4H), 3.47-3.39 (m, 4H), 3.34-3.31 (m, 2H), 2.35 (s, 3H), 1.91 (br.s., 2H), 1.36 (m, 1H). [M+H] _calcd for _{C23H23N5 370} ; found 370.

Preparation 48: 4-[6-(4-Cyanophenyl)-5-(4-methylphenyl)pyrazolo[4,3-b]pyridin-1-yl]piperidine-1-carboxylic acid tert-butyl ester

To 4-[5-(4-methylphenyl)-1H-pyrazolo[4,3-b]pyridin-6-yl]benzonitrile (80 mg, 0.258 mmol) and 4-bromopiperidine-1 - A mixture of tert-butyl carboxylate (341 mg, 1.29 mmol) in DMF (10 mL) was added _{Cs2CO3 (} 252 mg, 0.77 mmol). The mixture was stirred at 60°C overnight. The mixture was diluted with EtOAc (30 mL) and water (30 mL). The aqueous layer was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with water (30 mL x 2), brine, dried _{over Na2SO4} , filtered, concentrated and purified by preparative HPLC to give 48 mg (38%) of the title compound as a white solid. ¹ H NMR (CDCl ₃ , 400MHz) δ 8.32(s, 1H), 7.78(s, 1H), 7.59(d, J=8.4Hz, 2H), 7.35(d, J=8.4Hz, 2H), 7.19 (d,J=8.0Hz,2H),7.07(d,J=8.0Hz,2H),4.64-4.58(m,1H),4.36-4.32(m,2H),3.00-2.95(m,2H), 2.34(s, 3H), 2.30-2.23(m, 2H) 2.07(d, J=10.8Hz, 2H), 1.50(s, 9H). [M ₊ H] _calcd for _{C30H31N5O2 494} ; found 494.

Example 48: 4-[5-(4-Methylphenyl)-1-piperidin-4-ylpyrazolo[4,3-b]pyridin-6-yl]benzonitrile

The title compound was prepared according to the procedure used to prepare Example 3 from 4-[6-(4-cyanophenyl)-5-(4-methylphenyl)pyrazolo[4,3-b]pyridine-1- tert-butyl]piperidine-1-carboxylate was prepared as the HCl salt in 75% yield. ¹ H NMR(DMSO-d6,400MHz)δ9.67-9.64(brs,1H),9.50-9.48(brs,1H),8.45(s,1H),8.43(s,1H),7.81(d,J= 8.4Hz, 2H), 7.25 (d, J=8.4Hz, 2H), 7.16 (d, J=8.4Hz, 2H), 7.09 (d, J=8.0Hz, 2H), 5.18-5.13 (m, 1H) , 3.45-3.41(m, 2H), 3.12-3.08(m, 2H), 2.50-2.45(m, 2H), 2.27(s, 3H), 2.15-2.13(m, 2H). [M+H] _calcd for _C25H23N 394; found 394.

Preparation 49A: tert-butyl N-[1-(6-chloropyrazin-2-yl)piperidin-4-yl]carbamate

2,6-Dichloropyrazine (5.0 g, 33.6 mmol), 4-(N-Boc-amino)piperidine (6.7 g, 33.6 mmol) and _Et3N (4.7 mL) in NMP (50 mL) , 33.6 mmol) round bottom flask was heated to 120 °C for 2 hours. The resulting mixture was poured into ice water and extracted with ethyl acetate (3*100 mL). The organic layer was washed with brine, dried _{over Na2SO4} , and concentrated in vacuo. The residue was triturated with PE/MTBE (5:1) to provide crude tert-butyl N-[1-(6-chloropyrazin-2-yl)piperidin-4-yl]carbamate as an off-white solid ester (7.9 g, 75%). ¹ H NMR (300MHz, CDCl ₃ ): δ 1.38-1.45(2H,m), 1.45(9H,s) 2.04-2.09(2H,m), 3.01-3.10(2H,m), 3.69-3.74(1H) ,m), 4.20-4.27(2H,m), 4.46-4.49(1H,m), 7.78(1H,s), 7.98(1H,s). [M ₊ H] _calcd for _C14H21ClN4O2 313 _; found 313.

Preparation 49B: tert-butyl N-{1-[6-(4-cyano-3-fluorophenyl)pyrazin-2-yl]piperidin-4-yl}carbamate

To tert-butyl N-[1-(6-chloropyrazin- ₂ -yl)piperidin-4-yl]carbamate (1.0 g, A 3.21 mmol) round bottom flask was charged with (4-cyano-3-fluorophenyl)boronic acid (0.64 g, 3.85 mmol), Pd(OAc) ₂ (36 mg, 0.16 mmol), PPh ₃ (85 mg, 0.32 mmol) and _{K3PO4 (} 1.0 g, 4.82 mmol). The reaction mixture was kept at reflux for 16 hours under a nitrogen atmosphere. After completion, the mixture was poured into ice water and filtered. The filter cake was dissolved in ethyl acetate and washed successively with brine, dried _{over Na2SO4} , and concentrated in vacuo. The residue was triturated with PE to provide tertiary N-{1-[6-(4-cyano-3-fluorophenyl)pyrazin-2-yl]piperidin-4-yl}carbamic acid as an off-white solid Butyl ester (1.2 g, 94%). [ _M +H] _calcd for _{C21H24FN5O2 398} ; found 398.

Preparation 49C: tert-butyl N-{1-[5-bromo-6-(4-cyano-3-fluorophenyl)pyrazin-2-yl]piperidin-4-yl}carbamate

To tert-butyl N-{1-[6-(4-cyano-3-fluorophenyl)pyrazin-2-yl]piperidin-4-yl}carbamate (1.2) loaded in can (25 mL) g, 3.1 mmol) in a round bottom flask was added dropwise NBS (0.61 g, 3.4 mmol) in ACN (5 mL). The mixture was stirred at ambient temperature for 2 hours. After completion, the reaction mixture was quenched with water and extracted with ethyl acetate (3*50 mL). The organic layer was washed successively with water, brine, dried _{over Na2SO4} , and concentrated in vacuo. The residue was triturated with PE/MTBE (5:1) to afford crude N-{1-[5-bromo-6-(4-cyano-3-fluorophenyl)pyrazine- as a yellow solid 2-yl]piperidin-4-yl]carbamate tert-butyl ester (0.63 g, 43%). ¹ H NMR (400MHz, CDCl ₃ ): δ 1.37-1.45(2H,m), 1.45(9H,s) 2.07-2.10(2H,m), 3.04-3.11(2H,m), 3.70-3.75(1H) ,m), 4.23-4.26(2H,m), 4.47-4.49(1H,m), 7.63(1H,d,J=9.6Hz), 7.68-7.72(2H,m), 7.93(1H,s). [M ₊ H] _calcd for _{C21H23BrFN5O2 476} ; found 476.

Example 49. 4-[6-(4-Aminopiperidin-1-yl)-3-(2-methyl-2H-indazol-5-yl)pyrazin-2-yl]-2-fluorobenzonitrile

To N-{1-[5-bromo-6-(4-cyano-3-fluorophenyl)pyrazin-2-yl]piperidine loaded in ACN/ _H2O (3:1, 48 mL) To a round bottom flask was added (2-methyl-2H-indazol-5-yl)boronic acid (0.45 g, 2.56 mmol), Pd(OAc ) ₂ (14 mg, 0.063 mmol), S-PHOS (54 mg, 0.13 mmol) and K ₃ PO ₄ (0.67 g, 3.15 mmol). The mixture was heated to reflux under nitrogen atmosphere for 16 hours. After completion, the reaction mixture was poured into ice water and filtered. The filter cake was dissolved in ethyl acetate, washed successively with brine, dried _{over Na2SO4} , and concentrated in vacuo. The residue was purified by column chromatography (gradient of 50-100% ethyl acetate in PE) and preparative HPLC to give a yellow solid. The solid was suspended in ethyl acetate, then HCl (6 mL, 10 M in ethyl acetate) was added and stirring was continued at ambient temperature for 2 hours. After completion, the reaction mixture was concentrated in vacuo to provide the title compound as a yellow solid (0.22 g, 37%). ¹ H NMR (400MHz, CD ₃ OD): δ 1.73-1.81(2H,m), 2.20-2.22(2H,m), 3.22-3.28(2H,m), 3.51-3.57(1H,m), 4.37 (3H,s),4.70-4.73(2H,m),7.37(1H,d,J=7.6Hz),7.51(1H,d,J=9.6Hz),7.56(1H,d,J=8.8Hz) , 7.66(1H,dd,J=7.2Hz,7.6Hz), 7.71(1H,d,J=8.8Hz), 8.01(1H,s), 8.52(1H,s), 8.73(1H,s). [ _M +H] calcd for _{C24H22FN7 428} ; found 428.

Preparation 50A. Tert-butyl N-[1-(6-chloropyrazin-2-yl)piperidin-4-yl]N-methylcarbamate

Loaded with 2,6-dichloropyrazine (1.0 g, 6.7 mmol), 4-(N-Boc-methylamino)piperidine (1.43 g, 6.7 mmol) and DIEA (1.7 mmol) in DMF (20 mL) g, 13 mmol) in a round bottom flask (mL) was kept at 100°C for 2 hours. The resulting mixture was poured into ice water and extracted with ethyl acetate (3*100 mL). The organic layer was washed successively with brine, dried _{over Na2SO4} , and concentrated in vacuo. The residue was triturated with PE to provide crude tert-butyl N-[1-(6-chloropyrazin-2-yl)piperidin-4-yl]N-methylcarbamate as an off-white solid (2.1 g, 96%). ¹ H NMR (300MHz, CDCl ₃ ): δ 1.48(9H,s) 1.65-1.80(4H,m), 2.72(3H,s), 2.92-3.00(2H,m), 4.12-4.37(1H,m) ), 4.40-4.46(2H,m), 7.78(1H,s), 7.99(1H,s). [M ₊ H] _calcd for _{C15H23ClN4O2 327} ; found 327.

Prepare 50B. tert-butyl N-{1-[6-(4-cyano-3-fluorophenyl)pyrazin-2-yl]piperidin-4-yl}-N-methylcarbamate

To tert-butyl N-[1-(6-chloropyrazin-2-yl)piperidin-4-yl]N-methylcarbamate loaded in ACN/ _H2O (3:1, 40 mL) (2.1 g, 6.4 mmol, 1.0 equiv) round bottom flask was charged with (4-cyano-3-fluorophenyl)boronic acid (1.27 g, 7.7 mmol), Pd(OAc) ₂ (72 mg, 0.32 mmol), PPh ₃ (170 mg, 0.64 mmol) and _{K3PO4 (} 2.0 g, 9.64 mmol). The reaction mixture was kept at reflux for 16 hours under a nitrogen atmosphere. After completion, the mixture was poured into ice water and filtered. The filter cake was dissolved in ethyl acetate, washed successively with brine, dried _{over Na2SO4} , and concentrated in vacuo. The residue was triturated with PE to provide N-{1-[6-(4-cyano-3-fluorophenyl)pyrazin-2-yl]piperidin-4-yl}-N- as a yellow solid tert-Butyl methylcarbamate (2.3 g, 87%). ¹ H NMR (300MHz, CDCl ₃ ): δ 1.48(9H,s), 1.68-1.84(4H,m), 2.72(3H,s), 2.96-3.05(2H,m), 4.25-4.32(1H, m), 4.53-4.60(2H,m), 7.69(1H,dd,J=6.6Hz,8.1Hz), 7.84-7.90(2H,m), 8.19(1H,s), 8.29(1H,s). [M ₊ H] _calcd for _{C22H26FN5O2 412} ; found 412.

Preparation of 50C. N-{1-[5-Bromo-6-(4-cyano-3-fluorophenyl)pyrazin-2-yl]piperidin-4-yl-N-methyl}carbamic acid tert-butyl ester

To N-{1-[6-(4-cyano-3-fluorophenyl)pyrazin-2-yl]piperidin-4-yl}-N-methylcarbamic acid loaded in ACN (25 mL) To a round bottom flask of tert-butyl ester (2.3 g, 5.6 mmol) was added NBS (1.0 g, 5.6 mmol) in ACN (5 mL) dropwise. The mixture was stirred at ambient temperature for 2 hours. After completion, the reaction mixture was extracted with ethyl acetate (3*100 mL), and the organic layer was washed successively with brine, dried _{over Na2SO4} , and concentrated in vacuo. The residue was triturated with PE/MTBE (5:1) to afford crude N-{1-[5-bromo-6-(4-cyano-3-fluorophenyl)pyrazine- as a yellow solid 2-yl]piperidin-4-yl-N-methyl}carbamic acid tert-butyl ester (2.0 g, 73% yield). ¹ H NMR (400MHz, CDCl ₃ ): δ 1.47(9H,s), 1.63-1.81(4H,m), 2.72(3H,s), 2.94-3.01(2H,m), 4.23-4.28(1H, m), 4.41-4.45(2H,m), 7.64(1H,d,J=10.0Hz), 7.69-7.71(2H,m), 7.94(1H,s). [M ₊ H] _calcd for _{C22H25BrFN7O2 490} ; found 490.

Example 50. 2-Fluoro-4-[3-(2-methyl-2H-indazol-5-yl)-6-[4-(methylamino)piperidin-1-yl]pyrazin-2-yl ] benzonitrile

To N-{1-[5-bromo-6-(4-cyano-3-fluorophenyl)pyrazin-2-yl]piperidine loaded in ACN/ _H2O (3:1, 80 mL) To a round bottom flask was added (2-methyl-2H-indazol-5-yl)boronic acid (0.54 g, 3.06 mmol) to tert-butyl pyridin-4-yl}-N-methylcarbamate (1 g, 2.04 mmol) , Pd(OAc) ₂ (23 mg, 0.10 mmol), S- _PHOS (84 mg, 0.20 mmol) and _K3PO4 (0.86 g, 4.0 mmol). The mixture was kept at reflux and under a nitrogen atmosphere for 16 hours. After completion, the reaction mixture was poured into ice water and filtered. The filter cake was dissolved in ethyl acetate, washed successively with brine, dried _{over Na2SO4} , and concentrated in vacuo. The residue was purified by column chromatography (gradient of 50-100% ethyl acetate in PE) and preparative HPLC to give a yellow solid. The solid was suspended in ethyl acetate, then HCl (6 mL, 10M HCl-ethyl acetate) was added and stirring was continued at ambient temperature for 2 hours. After completion, the reaction was concentrated in vacuo to provide the title compound as the HCl salt (0.25 g, 27%). ¹ H NMR (300 MHz, CD ₃ OD): δ 1.77-1.81(2H,m), 2.30-2.34(2H,m), 2.78(3H,s), 3.20-3.28(2H,m), 3.31-3.33 (1H,m), 4.37(3H,s), 4.72-4.77(2H,m), 7.37(1H,d,J=6.9Hz), 7.49-7.54(2H,m), 7.63-7.72(2H,m) ), 8.01(1H,s), 8.52(1H,s), 8.70(1H,s). [ _M +H] calcd for _{C25H24FN7 442} ; found 442.

Example 51. 4-[6-(4-Aminopiperidin-1-yl)-3-(1-methyl-1H-indazol-5-yl)pyrazin-2-yl]-2-fluorobenzonitrile

N-{1-[5-Bromo-6-(4-cyano-3-fluorophenyl)pyrazin-2-yl]piperidin-4-yl}carbamic acid according to the procedure used to prepare Example 49 The HCl salt of the title compound was prepared in 48% yield starting from tert-butyl ester and (1-methyl-1H-indazol-5-yl)boronic acid. ¹ H NMR (400MHz, CD ₃ OD): δ 1.64-1.67(2H,m), 2.09-2.11(2H,m), 3.11-3.17(2H,m), 3.41-3.44(1H,m), 3.99 (3H,s),4.58-4.62(2H,m),7.20-7.26(2H,m),7.39(1H,d,J=6.8Hz),7.48-7.54(2H,m),7.77(1H,s) ), 7.97(1H,s), 8.38(1H,s). [ _M +H] calcd for _{C24H22FN7 428} ; found 428.

Example 52. 4-[6-(4-Aminopiperidin-1-yl)-3-(2-methyl-2H-indazol-6-yl)pyrazin-2-yl]-2-fluorobenzonitrile

N-{1-[5-Bromo-6-(4-cyano-3-fluorophenyl)pyrazin-2-yl]piperidin-4-yl}carbamic acid was used according to the procedure used to prepare Example 49 tert-Butyl ester and (2-methyl-2H-indazol-6-yl)boronic acid prepared the HCl salt of the title compound in 33% yield. ¹ H NMR (400 MHz, CD ₃ OD): δ 1.69-1.79(2H,m), 2.19-2.23(2H,m), 3.18-3.26(2H,m), 3.50-3.53(1H,m), 4.34 (3H,s),4.71-4.74(2H,m),7.25-7.30(1H,m),7.38-7.40(1H,m),7.50-7.53(1H,m),7.64-7.75(2H,m) , 7.84-7.90(1H,m), 8.49(1H,d,J=8.4Hz), 8.66(1H,s). [ _M +H] calcd for _{C24H22FN7 428} ; found 428.

Example 53. 4-[6-(4-Aminopiperidin-1-yl)-3-(1-methyl-1H-1,2,3-benzotriazol-5-yl)pyrazin-2-yl ]-2-Fluorobenzonitrile

N-{1-[5-Bromo-6-(4-cyano-3-fluorophenyl)pyrazin-2-yl]piperidin-4-yl}carbamic acid was used according to the procedure used to prepare Example 49 tert-Butyl ester and (1-methylbenzotriazol-5-yl)boronic acid prepared the HCl salt of the title compound in 39% yield. ¹ H NMR (300 MHz, CD ₃ OD): δ 1.63-1.76(2H,m), 2.14-2.19(2H,m), 3.12-3.20(2H,m), 3.45-3.50(1H,m), 4.34 (3H,s),4.66-4.71(2H,m),7.30(1H,dd,J=1.5Hz,8.1Hz),7.48(1H,dd,J=1.5Hz,10.2Hz),7.53(1H,dd ,J=1.5Hz,8.7Hz),7.60(1H,dd,J=6.6Hz,8.1Hz),7.73(1H,d,J=8.7Hz),7.96(1H,s),8.44(1H,s) . [M+H] _calcd for _{C23H21FN8 429} ; found 429.

Example 53. 4-[6-(4-Aminopiperidin-1-yl)-3-{3-methyl-3H-[1,2,3]triazolo[4,5-b]pyridine-6- yl}pyrazin-2-yl]-2-fluorobenzonitrile

N-{1-[5-Bromo-6-(4-cyano-3-fluorophenyl)pyrazin-2-yl]piperidin-4-yl}carbamic acid was used according to the procedure used to prepare Example 49 tert-Butyl ester and 4,4,5,5-tetramethyl-2-(3-methyl(1,2,3-triazolino[5,4-b]pyridin-6-yl))-1 ,3,2-dioxaborane prepared the HCl salt of the title compound in 8% yield. ¹ H NMR (400MHz, DMSO-d ₆ ): δ 1.56-1.65(2H,m), 2.05-2.08(2H,m), 3.07-3.14(2H,m), 3.37-3.39(1H,m), 4.30(3H,s),4.54-4.57(2H,m),7.31-7.33(1H,d,J=8.4Hz),7.67(1H,d,J=10.0Hz),7.80-7.84(1H,m) , 8.30(3H,br), 8.40(1H,s), 8.61(1H,s), 8.66(1H,s). [ _M +H] calcd for _{C22H20FN 9} 430; found 430.

Example 55. 4-[6-(4-Aminopiperidin-1-yl)-3-{1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl}pyrazin-2-yl ]-2-Fluorobenzonitrile

N-{1-[5-Bromo-6-(4-cyano-3-fluorophenyl)pyrazin-2-yl]piperidin-4-yl}carbamic acid was used according to the procedure used to prepare Example 49 tert-Butyl ester and 4,4,5,5-tetramethyl-2-(1-methylpyrrolo[2,3-b]pyridin-5-yl)-1,3,2-dioxolane Borane prepared the HCl salt of the title compound in 53% yield. ¹ H NMR (400 MHz, CD ₃ OD): δ 1.71-1.74(2H,m), 2.19-2.22(2H,m), 3.16-3.22(2H,m), 3.50-3.54(1H,m), 4.03 (3H,s),4.71-4.74(2H,m),6.81(1H,s),7.39(1H,d,J=8.0Hz),7.61(1H,d,J=10.0Hz),7.67-7.71( 2H,m), 8.41 (1H,s), 8.50-8.52 (2H,m). [ _M +H] calcd for _{C24H22FN7 428} ; found 428.

Example 56. 2-Fluoro-4-{6-[4-(methylamino)piperidinyl]-3-(1-methylbenzotriazol-5-yl)pyrazin-2-yl}benzonitrile

(tert-Butoxy)-N-{1-[5-bromo-6-(4-cyano-3-fluorophenyl)pyrazin-2-yl](4-bromo-6-(4-cyano-3-fluorophenyl)pyrazin-2-yl](4 -piperidinyl)}-N-methylformamide and (1-methylbenzotriazol-5-yl)boronic acid to prepare the HCl salt of the title compound in 80% yield. ¹ H NMR (400MHz, CD ₃ OD): δ 1.68-1.78(2H,m), 2.25-2.30(2H,m), 2.77(3H,s), 3.16-3.23(2H,m), 3.42-3.49 (1H,m), 4.37(3H,s), 4.72-4.86(2H,m), 7.31(1H,d,J=8.0Hz), 7.50(1H,d,J=10.4Hz), 7.53(1H, d, J=8.8 Hz), 7.62 (1H, dd, J=6.8 Hz, 8.0 Hz), 7.79 (1H, d, J=8.8 Hz), 8.05 (1H, s), 8.50 (1H, s). [ _M +H] calcd for _{C24H23FN8 443} ; found 443.

Example 57. 4-{3-[6-(Dimethylamino)(3-pyridyl)]-6-[4-(methylamino)piperidinyl]pyrazin-2-yl}-2-fluorobenzene Formonitrile

(tert-Butoxy)-N-{1-[5-bromo-6-(4-cyano-3-fluorophenyl)pyrazin-2-yl](4-bromo-6-(4-cyano-3-fluorophenyl)pyrazin-2-yl](4 -piperidinyl)}-N-methylformamide and (6-dimethylamino-pyridin-3-yl)boronic acid to prepare the title compound as the HCl salt in 77% yield. ¹ H NMR (400MHz, CD ₃ OD): δ 1.61-1.72(2H,m), 2.22-2.27(2H,m), 2.76(3H,s), 3.08-3.15(2H,m), 3.30(6H) ,s),3.36-3.45(1H,m),4.68-4.73(2H,m),7.17(1H,dd,J=9.2Hz,1.6Hz),7.47(1H,dd,J=1.2Hz,8.0Hz) ),7.61(1H,dd,J=1.2Hz,10.4Hz),7.78(1H,dd,J=6.8Hz,8.0Hz),7.84-7.87(1H,m),7.87(1H,s),8.45( 1H,s). [ _M +H] calcd for _{C24H26FN7 432} ; found 432.

Example 58. 4-{3-[2-(Dimethylamino)pyrimidin-5-yl]-6-[4-(methylamino)piperidinyl]pyrazin-2-yl}-2-fluorobenzyl Nitrile

(tert-Butoxy)-N-{1-[5-bromo-6-(4-cyano-3-fluorophenyl)pyrazin-2-yl]( 4-Piperidinyl)}-N-methylformamide and dimethyl-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxolane-2 -yl)-pyrimidin-2-yl]-amine The title compound was prepared as the HCl salt in 59% yield. ¹ H NMR (400MHz, CD ₃ OD): δ 1.61-1.71(2H,m), 2.22-2.27(2H,m), 2.76(3H,s), 3.30(6H,s), 3.08-3.14(2H) ,m),3.36-3.44(1H,m),4.67-4.73(2H,m),7.50(1H,dd,J=1.2Hz,8.0Hz),7.64(1H,dd,J=1.2Hz,10.4Hz) ), 7.78(1H,dd,J=6.8Hz,8.0Hz), 8.42(2H,s), 8.46(1H,s). [M+H] _calcd for _{C23H25FN8 433} ; found 433.

Example 59. 2-Fluoro-4-{6-[4-(methylamino)piperidinyl]-3-(1-methylpyrazolo[5,4-b]pyridin-5-yl)pyrazine- 2-yl}benzonitrile

(tert-Butoxy)-N-{1-[5-bromo-6-(4-cyano-3-fluorophenyl)pyrazin-2-yl](4-bromo-6-(4-cyano-3-fluorophenyl)pyrazin-2-yl](4 -Piperidinyl)}-N-methylformamide and 4,4,5,5-tetramethyl-2-(1-methylpyrazolo[5,4-b]pyridin-5-yl)- 1,3,2-Dioxaborane prepared the HCl salt of the title compound in 91% yield. ¹ H NMR (400MHz, CD ₃ OD): δ 1.67-1.71(2H,m), 2.25-2.28(2H,m), 2.79(3H,s), 3.10-3.14(2H,m), 3.42-3.44 (1H,m),4.12(3H,s),4.71-4.75(2H,m),7.30(1H,dd,J=1.6Hz,8.0Hz),7.54(1H,dd,J=1.2Hz,10.4Hz) ), 7.63(1H,dd,J=0.8Hz,6.8Hz), 8.08(1H,s), 8.21(1H,s), 8.47(1H,s), 8.48(s,1H). [ _M +H] calcd for _{C24H23FN8 443} ; found 443.

Example 60. 4-6-[4-(Dimethylamino)piperidinyl]-3-(2-methyl(2H-indazol-5-yl))pyrazin-2-yl}-2-fluorobenzene Formonitrile

4-{6-[4-(Dimethylamino)piperidinyl]-3-bromopyrazin-2-yl}-2-fluorobenzonitrile and (2- Methyl-2H-indazol-5-yl)boronic acid prepared the HCl salt of the title compound in 13% yield. ¹ HNMR (400MHz, CD ₃ OD): δ 1.79-1.83(2H,m), 2.22-2.25(2H,m), 2.94(6H,s), 3.08-3.14(2H,m), 3.57-3.58( 1H,m),4.23(3H,s),4.77-4.81(2H,m),7.28(1H,dd,J=1.6Hz,9.2Hz),7.34(1H,dd,J=1.2Hz,8.0Hz) , 7.52(1H,dd,J=1.2Hz,10.4Hz), 7.57-7.63(2H,m), 7.69(1H,s), 8.21(1H,s), 8.42(1H,s). [M+H] _calcd for _{C26H26FN7 456} ; found 456.

Example 61. 2-Fluoro-4-[3-(6-Fluoro-1-methylbenzimidazol-5-yl)-6-[4-(methylamino)piperidin-1-yl]pyrazine-2 -yl]benzonitrile

(tert-Butoxy)-N-{1-[5-bromo-6-(4-cyano-3-fluorophenyl)pyrazin-2-yl](4-bromo-6-(4-cyano-3-fluorophenyl)pyrazin-2-yl](4 -Piperidinyl)}-N-methylformamide and 6-fluoro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxolane Alk-2-yl)-1H-1,3-benzodiazole prepared the title compound as the HCl salt in 53% yield. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.51-1.66(m, 2H), 2.07-2.24(m, 2H), 2.59(s, 3H), 2.99-3.15(m, 2H), 3.95(s, 3H), 4.57-4.69(m, 2H), 7.26-7.36(m, 1H), 7.53-7.61(m, 1H), 7.63-7.76(m, 1H), 7.77-7.87(m, 1H), 7.92- 8.02 (m, 1H), 8.49-8.64 (m, 1H), 8.80-8.95 (m, 2H), 9.02-9.17 (m, 1H). [M ₊ H] _calcd for _{C25H23F2N7 460} ; found 460.

Example 62. 4-[3-(6,7-Difluoro-1-methylbenzimidazol-5-yl)-6-[4-(methylamino)piperidin-1-yl]pyrazine-2- base]-2-fluorobenzonitrile

(tert-Butoxy)-N-{1-[5-bromo-6-(4-cyano-3-fluorophenyl)pyrazin-2-yl](4-bromo-6-(4-cyano-3-fluorophenyl)pyrazin-2-yl](4 -Piperidinyl)}-N-methylformamide and 6,7-difluoro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxa Cyclopentaboran-2-yl)-1H-1,3-benzodiazole prepared the title compound as the HCl salt in 37% yield. ¹ HNMR (400MHz, DMSO-d ₆ ) δppm 1.46-1.70(m, 2H), 1.99-2.25(m, 2H), 2.59(s, 3H), 2.95-3.16(m, 2H), 3.26-3.54(m ,2H),4.00(s,3H),4.51-4.69(m,2H),7.21-7.38(m,1H),7.42-7.66(m,2H),7.77-7.86(m,1H),8.22-8.44 (s, 1H), 8.54-8.64 (s, 1H), 8.72-8.88 (m, 2H). [ _M +H] _calcd for _{C25H22F3N7 478} ; found 478.

Example 63. 2-Fluoro-4-[6-[4-(methylamino)piperidin-1-yl]-3-(1-prop-2-ylbenzimidazol-5-yl)pyrazine-2- base]benzonitrile

(tert-Butoxy)-N-{1-[5-bromo-6-(4-cyano-3-fluorophenyl)pyrazin-2-yl](4- piperidinyl)}-N-methylformamide and (3-fluoro-4-methoxyphenyl)boronic acid to prepare the HCl salt of the title compound in 94% yield. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.46-1.70 (m, 2H), 1.99-2.25 (m, 2H), 2.55-2.64 (m, 3H), 2.95-3.16 (m, 2H), 3.26 -3.54(m, 2H), 4.00(s, 3H), 4.51-4.69(m, 2H), 7.21-7.38(m, 1H), 7.42-7.66(m, 2H), 7.77-7.86(m, 1H) , 8.22-8.44 (m, 1H), 8.54-8.64 (m, 1H), 8.72-8.88 (m, 2H). [ _M +H] _calcd for _{C24H23F2N5O 436} ; found 436.

Example 64. 2-Fluoro-4-[3-[2-(1-hydroxycyclopentyl)ethynyl]-6-[4-(methylamino)piperidin-1-yl]pyrazin-2-yl] benzonitrile

4-{3-Bromo-6-[4-(methylamino)piperidin-1-yl]pyrazin-2-yl}-2-fluorobenzonitrile and 1 -Ethynylcyclopentan-1-ol The title compound was prepared in 25% yield. ¹ H NMR (400 MHz, CDCl ₃ ) δppm 1.36-1.56 (m, 2H), 1.69-1.82 (m, 2H), 1.82-1.92 (m, 2H), 2.03-2.12 (m, 2H), 2.43-2.57 ( m,6H),2.66-2.80(m,1H),2.85-3.00(m,2H),3.05-3.24(m,2H),4.29-4.45(m,2H),7.18-7.34(m,1H), 7.57-7.78 (m, 1H), 7.90-8.05 (m, 2H), 8.09-8.20 (m, 1H). [ _M +H] calcd for _{C24H26FN5O 420} ; found 420.

Example 65. 2-Fluoro-4-[6-[4-(methylamino)piperidin-1-yl]-3-(1-methylbenzimidazol-5-yl)pyrazin-2-yl]benzene Formonitrile

(tert-Butoxy)-N-{1-[5-bromo-6-(4-cyano-3-fluorophenyl)pyrazin-2-yl](4-bromo-6-(4-cyano-3-fluorophenyl)pyrazin-2-yl](4 -Piperidinyl)}-N-methylformamide and 6,7-difluoro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxa Cyclopentaboran-2-yl)-1H-1,3-benzodiazole prepared the title compound as the HCl salt in 48% yield. ¹ HNMR (400MHz, DMSO-d ₆ ) δppm 1.50-1.77(m, 2H), 2.11-2.21(m, 2H), 2.56(br.s., 3H), 2.95-3.12(m, 2H), 3.24- 3.39(m,1H), 3.43-3.82(m,1H), 4.05(s,3H), 4.56-4.65(m,2H), 7.17-7.38(m,1H), 7.41-7.54(m,1H), 7.56-7.71(m,1H), 7.78-7.90(m,3H), 8.52-8.64(m,1H), 9.06-9.25(br,2H), 9.49-9.59(s,1H). [ _M +H] calcd for _{C25H24FN7 442} ; found 442.

Example 66. 2-Fluoro-4-[3-(3-hydroxy-3-methylbut-1-ynyl)-6-[4-(methylamino)piperidin-1-yl]pyrazine-2- base]benzonitrile

4-{3-Bromo-6-[4-(methylamino)piperidin-1-yl]pyrazin-2-yl}-2-fluorobenzonitrile and 2 - Methylbut-3-yn-2-ol The title compound was prepared in 34% yield. ¹ H NMR (400MHz, CDCl ₃ ) δppm 1.39-1.50(m, 2H), 1.98-2.13(m, 2H), 2.17-2.39(m, 3H), 2.50(s, 3H), 2.71-2.80(m, 1H), 2.88(s, 3H), 2.96(s, 3H), 3.07-3.19(m, 2H), 4.26-4.46(m, 2H), 7.16-7.38(m, 1H), 7.57-7.76(m, 1H), 7.89-8.08 (m, 3H), 8.10-8.22 (m, 1H). [ _M +H] calcd for _{C22H24FN5O 394} ; found 394.

Example 67. 2-Fluoro-4-[3-(6-Fluoro-1-propan-2-ylbenzimidazol-5-yl)-6-[4-(methylamino)piperidin-1-yl]pyridine oxazin-2-yl]benzonitrile

(tert-Butoxy)-N-{1-[5-bromo-6-(4-cyano-3-fluorophenyl)pyrazin-2-yl](4-bromo-6-(4-cyano-3-fluorophenyl)pyrazin-2-yl](4 -Piperidinyl)}-N-methylformamide and 6-fluoro-1-(propan-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-di Oxaborolan-2-yl)-lH-l,3-benzodiazole prepared the title compound as the HCl salt in 46% yield. ¹ HNMR (400MHz, DMSO-d ₆ ) δppm 1.58(d, J=6.57Hz, 8H), 2.09-2.24(m, 2H), 2.56(br.s., 3H), 2.98-3.14(m, 2H) ),3.25-3.37(m,1H),3.41-3.80(m,1H),4.51-4.71(m,3H),4.79-5.06(m,2H),7.28-7.44(m,1H),7.53-7.64 (m,1H),7.77-7.95(m,2H),7.95-8.07(m,1H),8.54-8.67(m,1H),8.99-9.27(m,2H),9.46-9.65(m,1H) . [M ₊ H] _calcd for _{C27H27F2N7 488} ; found 488.

Example 68. 2-Fluoro-4-[6-[4-(methylamino)piperidin-1-yl]-3-(1-prop-2-ylbenzimidazol-5-yl)pyrazine-2- base]benzonitrile

(tert-Butoxy)-N-{1-[5-bromo-6-(4-cyano-3-fluorophenyl)pyrazin-2-yl](4-bromo-6-(4-cyano-3-fluorophenyl)pyrazin-2-yl](4 -Piperidinyl)}-N-methylformamide and 1-(propan-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxolane Boran-2-yl)-1H-1,3-benzodiazole prepared the title compound as the HCl salt in 49% yield. ¹ H NMR (400 MHz, methanol-d ₄ ) δppm 2.07-2.26 (m, 2H), 2.56-2.63 (m, 3H), 2.98-3.10 (m, 2H), 3.64-3.78 (m, 9H), 4.53- 4.69(m,2H),4.92-5.11(m,1H),7.29-7.36(m,1H),7.42-7.49(m,1H),7.60-7.69(m,2H),7.83-7.97(m,2H) ), 8.52-8.66 (m, 1H), 9.36-9.56 (m, 1H). [M+H] _calcd for _{C27H28FN7 470} ; found 470.

Example 69. 4-[3-(1-Ethyl-6-fluorobenzimidazol-5-yl)-6-[4-(methylamino)piperidin-1-yl]pyrazin-2-yl]- 2-Fluorobenzonitrile

(tert-Butoxy)-N-{1-[5-bromo-6-(4-cyano-3-fluorophenyl)pyrazin-2-yl](4-bromo-6-(4-cyano-3-fluorophenyl)pyrazin-2-yl](4 -Piperidinyl)}-N-methylformamide and 1-ethyl-6-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxolane Alk-2-yl)-1H-1,3-benzodiazole prepared the title compound as the HCl salt in 45% yield. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.49 (m, 3H), 1.55-1.71 (m, 2H), 2.10-2.23 (m, 2H), 2.58 (s, 3H), 2.95-3.13 (m, 2H), 3.27-3.40(m, 1H), 3.44-3.54(m, 2H), 3.65-3.76(m, 2H), 4.36-4.47(m, 2H), 4.55-4.68(m, 2H), 7.22- 7.40(m,1H),7.56-7.69(m,1H),7.84-7.95(m,2H),8.03(br.s.,1H),8.61(s.,1H),9.11(br.s., 2H), 9.46 (br.s., 1H). [M ₊ H] _calcd for _{C26H25F2N7 474} ; found 474.

Example 70. 4-[6-(4-Aminopiperidin-1-yl)-3-(6-fluoro-1-propan-2-ylbenzimidazol-5-yl)pyrazin-2-yl]-2 -Fluorobenzonitrile

N-{1-[5-Bromo-6-(4-cyano-3-fluorophenyl)pyrazin-2-yl]piperidin-4-yl}carbamic acid was used according to the procedure used to prepare Example 49 tert-Butyl ester and 6-fluoro-1-(propan-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl )-1H-1,3-benzodiazole to prepare the HCl salt of the title compound in 45% yield. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.601.46-1.74(m, 10H), 1.97-2.16(m, 2H), 3.00-3.17(m, 2H), 3.57(s, 3H), 3.60- 3.75(m, 2H), 4.48-4.67(m, 2H), 4.85-5.03(m, 1H), 7.25-7.42(m, 1H), 7.54-7.67(m, 1H), 7.76-7.97(m, 2H ), 7.97-8.06(m, 1H), 8.56-8.64(s, 1H), 9.46-9.61(m, 1H). [M ₊ H] _calcd for _{C26H25F2N7 474} ; found 474.

Example 71. 4-[6-(4-Aminopiperidin-1-yl)-3-(1-ethyl-6-fluorobenzimidazol-5-yl)pyrazin-2-yl]-2-fluorobenzene Formonitrile

N-{1-[5-Bromo-6-(4-cyano-3-fluorophenyl)pyrazin-2-yl]piperidin-4-yl}carbamic acid was used according to the procedure used to prepare Example 49 tert-Butyl ester and 1-ethyl-6-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-1 ,3-Benzodiazole to prepare the HCl salt of the title compound in 60% yield. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.40-1.55(m,3H), 1.55-1.70(m,2H), 1.97-2.15(m,2H), 3.01-3.23(m,3H), 3.66- 3.76(m, 2H), 4.35-4.50(m, 2H), 4.51-4.65(m, 2H), 7.30-7.41(m, 1H), 7.52-7.67(m, 1H), 7.78-7.94(m, 2H) ), 8.00-8.09 (m, 1H), 8.16-8.33 (m, 1H), 8.59 (br.s., 1H), 9.52 (br.s., 1H). [M ₊ H] _calcd for _{C25H23F2N7 460} ; found 460.

Example 72. 4-[6-(4-Aminopiperidin-1-yl)-3-(1-prop-2-ylbenzimidazol-5-yl)pyrazin-2-yl]-2-fluorobenzyl Nitrile

N-{1-[5-Bromo-6-(4-cyano-3-fluorophenyl)pyrazin-2-yl]piperidin-4-yl}carbamic acid was used according to the procedure used to prepare Example 49 tert-Butyl ester and 1-(propan-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H- 1,3-Benzodiazole was used to prepare the HCl salt of the title compound in 42% yield. ¹ H NMR (400 MHz, DMSO-d ₆ ) δppm 1.45-1.68 (m, 2H), 1.60 (d, J=6.82 Hz, 6H), 1.97-2.09 (m, 2H), 3.02-3.17 (m, 2H) ,3.44-3.52(m,2H),3.65-3.81(m,1H),4.47-4.71(m,2H),4.87-5.07(m,1H),7.22-7.35(m,1H),7.42-7.53( m,1H),7.56-7.68(m,1H),7.69-7.80(m,1H),7.80-7.89(m,1H),7.89-7.97(m,1H),8.50-8.64(m,1H), 9.40-9.54 (m, 1H). [M+H] _calcd for _{C26H26FN7 456} ; found 456.

Example 73. 4-[6-(4-Aminopiperidin-1-yl)-3-(6,7-difluoro-1-propan-2-ylbenzimidazol-5-yl)pyrazin-2-yl ]-2-Fluorobenzonitrile

N-{1-[5-Bromo-6-(4-cyano-3-fluorophenyl)pyrazin-2-yl]piperidin-4-yl}carbamic acid was used according to the procedure used to prepare Example 49 tert-Butyl ester and 6,7-difluoro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)- 1H-1,3-Benzodiazole was used to prepare the HCl salt of the title compound in 40% yield. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.47-1.62 (m, 2H), 1.56 (d, J=6.57Hz, 6H), 1.97-2.10 (m, 2H), 2.99-3.17 (m, 2H) ,3.45-3.53(m,2H),3.61-3.76(m,2H),4.47-4.66(m,2H),4.75-5.01(m,1H),7.18-7.38(m,1H),7.52-7.68( m, 2H), 7.77-7.89 (m, 1H), 7.89-8.03 (m, 1H), 8.42-8.69 (m, 2H). _{[ M} +H] calcd for _{C26H24F3N7 492} ; found 492.

Example 74. 4-[6-(4-Aminopiperidin-1-yl)-3-(1-ethyl-6,7-difluorobenzimidazol-5-yl)pyrazin-2-yl]-2 -Fluorobenzonitrile

N-{1-[5-Bromo-6-(4-cyano-3-fluorophenyl)pyrazin-2-yl]piperidin-4-yl}carbamic acid was used according to the procedure used to prepare Example 49 tert-Butyl ester and 1-ethyl-6,7-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)- 1H-1,3-Benzodiazole was used to prepare the HCl salt of the title compound in 64% yield. ¹ H NMR (400 MHz, DMSO-d ₆ ) δppm 1.49-1.58 (m, 3H), 1.58-1.73 (m, 2H), 1.98-2.18 (m, 2H), 2.97-3.19 (m, 2H), 3.54- 3.66(m,1H),3.66-3.76(m,2H),4.43-4.68(m,4H),7.22-7.38(m,1H),7.58-7.71(m,1H),7.74-7.91(m,2H ), 8.57-8.65 (m, 1H), 9.57 (br.s., 1H). [ _M +H] _calcd for _{C25H22F3N7 478} ; found 478.

Example 75. 4-[6-(4-Aminopiperidin-1-yl)-3-(6,7-difluoro-1-methylbenzimidazol-5-yl)pyrazin-2-yl]-2 -Fluorobenzonitrile

N-{1-[5-Bromo-6-(4-cyano-3-fluorophenyl)pyrazin-2-yl]piperidin-4-yl}carbamic acid was used according to the procedure used to prepare Example 49 tert-Butyl ester and 6,7-difluoro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)- 1H-1,3-Benzodiazole was used to prepare the HCl salt of the title compound in 51% yield. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.51-1.68 (m, 2H), 1.93-2.10 (m, 2H), 2.96-3.18 (m, 2H), 3.62-3.75 (m, 4H), 4.00 ( s(,3H),4.47-4.62(m,2H),7.22-7.35(m,1H),7.43-7.65(m,2H),7.75-7.78(m,1H),8.01-8.21(m,2H) , 8.40(s, 1H), 8.61(s, 1H). _{[ M} +H] calcd for _{C24H20F3N7 464} ; found 464.

II. Biological Evaluation

Example 1a: In vitro Enzyme Inhibition Assay - LSD-1

This assay determines the ability of test compounds to inhibit LSD1 demethylase activity. E. coli expressed full-length human LSD1 (Accession No. 060341) was purchased from Active Motif (Cat. No. 31334).

The enzymatic assay of LSD1 activity is based on Time Resolved-Fluorescence Resonance Energy Transfer (TR-FRET) assay. The inhibitory properties of compounds against LSD1 were determined in 384-well plate format under the following reaction conditions: 0.1 nM LSD1, 50 nM MH3K4me1-biotinylated peptide (Anaspec Cat. No. 64355), 2 μM FAD in 50 mM HEPES assay Buffer, pH 7.3, 10 mM NaCl, 0.005% Brij35, 0.5 mM TCEP, 0.2 mg/ml BSA. Detection reagent Phycolink Streptavidin-allophycocyanin is added in the presence of an LSD1 inhibitor such as 1.8 mM tranylcypromine hydrochloride (2-PCPA) in LANCE detection buffer (PerkinElmer) (Prozyme) and europium-anti-unmodified histone H3 lysine 4 (H3K4) antibody (PerkinElmer) to final concentrations of 12.5 nM and 0.25 nM, respectively, reaction products were quantified by TR-FRET.

The assay reaction was performed according to the following procedure: 2 μL of a mixture of 150 nM H3K4me1-biotin-labeled peptide and 2 μL of 11-point serial diluted test compound in 3% DMSO were added to each of the plates. 2 μL of 0.3 nM LSD1 and 6 μM FAD were subsequently added to initiate the reaction. Then, the reaction mixture was incubated at room temperature for one hour and detected by adding 6 μL of LANCE detection buffer containing 25 nM Phycolink Streptavidin-Allophycocyanin and 0.5 nM Europium-anti-unmodified H3K4 antibody was terminated with 1.8 mM 2-PCPA in . After 1 hour incubation at room temperature, plates were read by EnVision Multilabel Reader in TR-FRET mode (excitation at 320 nm, emission at 615 nm and 665 nm). The ratio (665/615) was calculated for each well and fitted to determine the inhibition constant ( _IC50 ).

The ability of the compounds disclosed herein to inhibit LSD1 activity was quantified, and respective _IC50 values were determined. Table 3 provides _IC50 values for various substituted heterocyclic compounds disclosed herein.

table 3

NOTE: Biochemical assay _IC50 data are specified within the following ranges:

A:≤100nM

B:>100nM to ≤1,000nM

C: >1,000nM to ≤10,000nM

D:>10,000nM

Example 2a: In vitro enzyme inhibition assay - MAO selectivity

Human recombinant monoamine oxidase proteins MAO-A and MAO-B were obtained. MAO catalyzes the oxidative deamination of primary, secondary and tertiary amines. To monitor MAO enzymatic activity and/or its rate of inhibition by inhibitors of interest, fluorescence-based (inhibitor)-screening assays were performed. 3-(2-Aminophenyl)-3-oxopropylamine (kynuraminedihydrobromide, Sigma Aldrich) (a non-fluorescent compound) was chosen as substrate. Kynurenine is a non-specific substrate for both MAO activities. When undergoing oxidative deamination through MAO activity, kynurenine is converted to 4-hydroxyquinoline (4-HQ), resulting in a fluorescent product.

Monoamine oxidase activity was assessed by measuring the conversion of kynurenine to 4-hydroxyquinoline. Assays were performed in 96-well black plates with clear bottoms (Corning) in a final volume of 100 μl. The assay buffer was 100 mM HEPES, pH 7.5. Each experiment was performed in triplicate in the same experiment.

Briefly, fixed amounts of MAO (0.25 μg for MAO-A, 0.25 μg for MAO-A, and For MAO-B, 0.5 μg) were incubated in reaction buffer on ice for 15 minutes. Tranylcypromine (Biomol International) was used as a control for inhibition.

After allowing the enzymes to interact with the test compounds, 60 μM to 90 μM of kynurenine was added to each reaction for MAO-B and MAO-A assays, respectively, and the reactions were placed in the dark at 37° C. for 1 hour. Oxidative deamination of the substrate was stopped by adding 50 μl of 2N NaOH. The conversion of kynurenine to 4-hydroxyquinoline was monitored by fluorescence (excitation at 320 nm, emission at 360 nm) using a microplate reader (Infinite 200, Tecan). Arbitrary units are used to measure the level of fluorescence produced in the absence and/or presence of the test compound.

The maximum value of the oxidative deamination activity was obtained by measuring the amount of 4-hydroxyquinoline formed from the deamination of kynurenine in the absence of the test compound and corrected for background fluorescence. The Ki ( _IC50 ) for each inhibitor was determined at _Vmax /2.

Example 3a: LSD1 CD11b Cell Assay

To analyze the efficacy of LSD1 inhibitors in cells, CD11b flow cytometry assays were performed. LSD1 inhibition induces CD11b expression in THP-1 (AML) cells, which can be measured by flow cytometry. THP-1 cells were seeded at 100,000 cells/well in 24-well plates in RPMI 1640 medium containing 10% fetal bovine serum and the final volume per well was 500 [mu]L. LSD1 test compounds were serially diluted in DMSO. Diluents were added to each well accordingly to a final concentration of 0.2% DMSO. Cells were incubated at 37 °C in 5% CO for ₄ days. Transfer 250 μL of each well to wells in a 96-well round bottom plate. Plates were centrifuged in a Beckman Coulter Alegra 6KR centrifuge at 1200 rpm for 5 minutes at 4 degrees Celsius. The medium was removed, leaving the cells at the bottom of the wells. Cells were washed in 100 μL of cold HBSS (Hank's Balanced Salt Solution) plus 2% BSA (Bovine Serum Albumin) solution and centrifuged at 1200 rpm for 5 minutes at 4 degrees Celsius. The laundry is removed. Cells were resuspended in 100 μL of HBSS plus 2% BSA containing a 1:15 dilution of APC-conjugated mouse anti-CD11b antibody (BD Pharmingen Cat. No. 555751) and incubated on ice for 25 minutes. Cells were centrifuged and washed twice in 100 μl HBSS plus 2% BSA. After the final spin, cells were resuspended in 100 μL HBSS plus 2% BSA containing 1 μg/mL DAPI (4',6-diamidino-2-phenylindole). Cells were then analyzed by flow cytometry in a BD FACSAria machine. Cells were analyzed for CD11b expression. For each inhibitor concentration, the percentage of cells expressing CD11b was used to determine the _IC50 curve for each compound used for analysis.

Table 4 provides cellular _IC50 values for various substituted heterocyclic compounds disclosed herein.

Table 4

NOTE: Cell assay _IC50 data are specified in the following ranges:

A:≤0.10μM C:>1.0μM to ≤10μM

B:>0.10μM to ≤1.0μM D:>10μM

Example 4a: In vivo xenograft studies - MCF-7 xenograft

Time release pellets containing 0.72 mg of 17-beta estradiol were implanted subcutaneously into nu/nu mice. MCF-7 cells were grown in RPMI containing 10% FBS at 5% _CO2 , 37°C. Cells were spin down and resuspended in 50% RPMI (serum free) and 50% Matrigel at ¹ x 107 cells/mL. MCF-7 cells were injected subcutaneously on the right side (100 μL/animal) 2-3 days after pellet implantation, and tumor volume (length x width ^2/2 ) was monitored biweekly. Animals were randomized and treatment started when tumors reached a mean volume of -200 ^mm3 . Animals are treated with vehicle or compound daily for 4 weeks. Tumor volume and body weight were monitored biweekly throughout the study. At the end of the treatment cycle, plasma and tumor samples were taken for pharmacokinetic and pharmacodynamic analysis, respectively.

Example 5a: In vivo xenograft studies - LNCaP xenografts

LNCaP cells with stable knockout of LSD1 (shLSD1 cells) or control cells (eg ^shNTC cells) were seeded in the dorsal flank of nude mice by subcutaneous injection (eg 3x10 cells in 100 μl of 50% RPMI1640/BD Matrigel). Mice body weight and tumor size were measured weekly, and tumor volume was assessed using formula (7i/6)(LxW), where L=tumor length and W=tumor width. Two-sample t-tests were performed to determine statistical differences in mean tumor volumes between the two groups.

Unmodified LNCaP cells were inoculated into the dorsal side of nude mice by subcutaneous injection (eg ³ x 106 cells in 100 μl of 50% RPMI 1640/BD Matrigel). After three weeks, mice were injected intraperitoneally once daily with water (control), pargyline (0.53 mg or 1.59 mg; 1 mM or 3 mM final concentration, assuming 70% bioavailability), or XB154 (4 μg or 20 μg; 1 μM or 5 μM final concentration, assuming 70% bioavailability) or treated with test compound (5 mg/kg per week or 10 mg/kg per week). Treatment continued for three weeks, during which time mouse body weight and tumor volume were measured as above.

shLSD1 LNCaP cells or control cells were injected in nude mice as above. After three weeks, mice were treated with 2.6 μg mitomycin C (predicted final concentration of 1 μM, assuming 40% bioavailability), olaparib (eg, about 0.5 mg/kg to 25 mg/kg) kg) or vehicle intraperitoneally once daily for three weeks. In other embodiments, unmodified LNCaP cells are injected in nude mice as above.

After three weeks, mice were treated with test compound or vehicle plus MMC or olaparib as above. Treatment continued for three weeks, during which time mouse body weight and tumor volume were measured as above.

The reduction in tumor volume in mice injected with shLSD1 cells compared to controls indicates that LSD1 inhibition reduces tumor growth in vivo.

Similarly, reduced tumor volume in mice injected with LNCaP cells and treated with compounds disclosed herein, compared to controls, indicates that LSD1 inhibition reduces tumor growth in vivo. Finally, a reduction in tumor volume in mice injected with LNCaP cells and treated with a compound disclosed herein plus olaparib compared to mice treated with a compound disclosed herein alone is indicative of inhibition of LSD1 plus PARP Inhibition reduces tumor growth in vivo.

The obtained xenograft tissues were examined for evidence of LSD1 inhibition. This was assessed with Western blots to examine overall levels of 2MK4 and 2MK9 histone markers, FA/BRCA gene expression, FANCD2 ubiquitination and LSD1 protein levels in the case of shRNA cells. A decrease in one or more of these parameters indicates effective suppression of LSD 1 . In addition, the effect on DNA damage repair was assessed by staining for H2AX foci.

III. Preparation of Pharmaceutical Dosage Forms

Example 1b: Oral tablet

Tablets by making 48% by weight of a compound of formula (I), formula (II) or formula (III) or a pharmaceutically acceptable salt thereof, 45% by weight of microcrystalline cellulose, 5% by weight of % of low-substituted hydroxypropyl cellulose and 2% by weight of magnesium stearate were mixed. Tablets are prepared by direct compression. The total weight of the compressed tablets was kept at 250-500 mg.

Claims (35)

1. A compound having the structure of formula (IV) or a pharmaceutically acceptable salt thereof,

wherein,

x and Y are each independently selected from C-H, C-F, C-CH₃Or N;

z is selected from-G, -CH₂-G、-CH₂-CH₂-G、–N(R¹)-G、–N(R¹)-CH₂-G、-O-G、-O-CH₂-G or-C (O) N (R)²)(R³)；

X¹、X²And X³Is any one of the following:

(i)X¹is N; x²Is N; and X³Is C-R⁴；

(ii)X¹Is N; x²Is C-R⁴(ii) a And X³Is C-R⁴；

(iii)X¹Is C-R⁴；X²Is N; and X³Is N;

(iv)X¹is C-R⁴；X²Is C-R⁴(ii) a And X³Is N;

(v)X¹is C-R⁴；X²Is N; and X³Is C-R⁴；

(vi)X¹Is N; x²Is N; and X³Is N;

g is carbocyclyl, aryl, heterocyclyl or heteroaryl;

R¹is hydrogen or alkyl;

R²and R³Independently selected from hydrogen, alkyl, heterocyclyl, heterocyclylalkyl, or optionally, R²And R³Linked to form an N-linked heterocyclyl ring system;

R⁴is hydrogen, halogen, C₁-C₃Alkyl or C₁-C₃An alkoxy group; and is

R is one of the following:

aryl, heteroaryl, alkynyl or cycloalkylalkynylene, at X¹、X²And X³Is any one of the following:

(ii)X¹is N; x²Is C-R⁴(ii) a And X³Is C-R⁴；

(iii)X¹Is C-R⁴；X²Is N; and X³Is N;

(iv)X¹is C-R⁴；X²Is C-R⁴(ii) a And X³Is N;

(v)X¹is C-R⁴；X²Is N; and X³Is C-R⁴；

(vi)X¹Is N; x²Is N; and X³Is N; or

Aryl or heteroaryl at (i) X¹Is N; x²Is N; and X³Is C-R⁴When the user wants to use the device.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R is aryl or heteroaryl.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein formula (IV) is formula (IVa):

4. the compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein formula (IV) is formula (IVb):

5. the compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein formula (IV) is formula (IVd):

6. the compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein formula (IV) is formula (IVe):

7. the compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein formula (IV) is formula (IVf):

8. the compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein formula (IV) is formula (IVg):

9. the compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X is C-H.

10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X is C-F.

11. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X is C-CH₃。

12. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X is N.

13. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Y is C-H.

14. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Y is C-F.

15. The compound of claim 1, or a pharmaceutically acceptable salt thereof, whichWherein Y is C-CH₃。

16. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Y is N.

17. The compound or pharmaceutically acceptable salt of claim 1, wherein X is C-H and Y is C-H.

18. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Z is selected from the group consisting of:

(a)-O-CH₂-G；

(b)-O-G；

(c)-N(R¹)-CH₂-G；

(d)-N(R¹)-G；

(e)-CH₂-CH₂-G；

(f)-CH₂-G; and

(g)-C(O)N(R²)(R³)。

19. the compound of claim 18, or a pharmaceutically acceptable salt thereof, wherein:

(a)R²and R³Independently selected from hydrogen or alkyl; or

(b)R²And R³Independently selected from heterocyclyl or heterocyclylalkyl; or

(c)R²And R³Are linked to form an N-linked heterocyclyl ring system.

20. The compound of claim 18, or a pharmaceutically acceptable salt thereof, wherein R¹Is hydrogen or alkyl.

21. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R⁴Is hydrogen or C₁-C₃An alkoxy group.

22. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein G is heterocyclyl.

23. The compound of claim 22, or a pharmaceutically acceptable salt thereof, wherein G is a nitrogen-containing heterocyclyl.

24. The compound of claim 23, or a pharmaceutically acceptable salt thereof, wherein the nitrogen-containing heterocyclic group is a five-membered heterocyclic group or a six-membered heterocyclic group.

25. The compound of claim 22, or a pharmaceutically acceptable salt thereof, wherein the heterocyclyl is selected from:

26. the compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R is selected from the group consisting of:

(a) a monocyclic nitrogen-containing heteroaryl group; and

(b) bicyclic nitrogen-containing heteroaryl.

27. The compound of claim 26, or a pharmaceutically acceptable salt thereof, wherein R is selected from:

28. the compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein the aryl is an optionally substituted phenyl group.

29. The compound of claim 28, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted phenyl group is selected from 4-methylphenyl, 4-chlorophenyl, 4-fluorophenyl, 4-cyanophenyl, 4- (methylsulfonyl) phenyl, or 4-trifluoromethylphenyl.

30. The compound of claim 28, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted phenyl group is selected from 4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, or 3-chloro-4-methoxyphenyl.

31. A compound selected from the group consisting of:

4- [5- (4-methylphenyl) -2- { [ (3S) -pyrrolidin-3-ylmethyl ] amino } pyrimidin-4-yl ] benzonitrile;

4- [5- (4-fluorophenyl) -2- { [ (3S) -pyrrolidin-3-ylmethyl ] amino } pyrimidin-4-yl ] benzonitrile;

4- [5- (4-chlorophenyl) -2- { [ (3S) -pyrrolidin-3-ylmethyl ] amino } pyrimidin-4-yl ] benzonitrile;

4- [5- (4-methylphenyl) -2- [ (3R) -pyrrolidin-3-ylmethoxy ] pyrimidin-4-yl ] benzonitrile;

4- {2- [ (3aR,6aS) -octahydropyrrolo [3,4-c ] pyrrol-2-yl ] -5- (4-methylphenyl) pyrimidin-4-yl } benzonitrile;

4- [5- (4-methylphenyl) -2- { octahydro-1H-pyrrolo [3,4-c ] pyridin-5-yl } pyrimidin-4-yl ] benzonitrile;

4- {2- [ (3aR,8aS) -decahydropyrrolo [3,4-d ] azepin-6-yl ] -5- (4-methylphenyl) pyrimidin-4-yl } benzonitrile;

4- {2- [ (3aR,8aS) -decahydropyrrolo [3,4-d ] azepin-6-yl ] -5- (4-fluorophenyl) pyrimidin-4-yl } benzonitrile;

4- (2- { [ (3S) -pyrrolidin-3-ylmethyl ] amino } -5- [4- (trifluoromethyl) phenyl ] pyrimidin-4-yl) benzonitrile;

4- [5- (2-cyclopropylethynyl) -2- { [ (3S) -pyrrolidin-3-ylmethyl ] amino } pyrimidin-4-yl ] benzonitrile;

4- (2- { [ (3aR,5S,6aS) -octahydrocyclopenta [ c ] pyrrol-5-yl ] amino } -5- (4-methylphenyl) pyrimidin-4-yl) benzonitrile;

(±) -4- (2- { [ (3-fluoropyrrolidin-3-yl) methyl ] amino } -5- (4-methylphenyl) pyrimidin-4-yl) benzonitrile;

(±) -4- [5- (4-methylphenyl) -2- [ (piperidin-3-yl) amino ] pyrimidin-4-yl ] benzonitrile;

4- [5- (4-methylphenyl) -2- [ (piperidin-4-yl) amino ] pyrimidin-4-yl ] benzonitrile;

(±) -4- [5- (4-methylphenyl) -2- [ (piperidin-3-ylmethyl) amino ] pyrimidin-4-yl ] benzonitrile;

4- [5- (4-methylphenyl) -2- [ (piperidin-4-ylmethyl) amino ] pyrimidin-4-yl ] benzonitrile;

(±) -4- [5- (4-methylphenyl) -2- [ (morpholin-2-ylmethyl) amino ] pyrimidin-4-yl ] benzonitrile;

(±) -4- [5- (4-fluorophenyl) -2- [ (morpholin-2-ylmethyl) amino ] pyrimidin-4-yl ] benzonitrile;

4- (2- {2, 7-diazaspiro [4.4] non-2-yl } -5- (4-methylphenyl) pyrimidin-4-yl) benzonitrile;

4- (2- {2, 8-diazaspiro [4.5] decan-2-yl } -5- (4-methylphenyl) pyrimidin-4-yl) benzonitrile;

4- [5- (4-methylphenyl) -2- { octahydro-1H-pyrrolo [3,4-c ] pyridin-2-yl } pyrimidin-4-yl ] benzonitrile;

4- [5- (4-methylphenyl) -2- { octahydro-1H-pyrrolo [3,2-c ] pyridin-5-yl } pyrimidin-4-yl ] benzonitrile;

4- (2- {2, 8-diazaspiro [4.5] decan-8-yl } -5- (4-methylphenyl) pyrimidin-4-yl) benzonitrile;

4- (2- {1, 8-diazaspiro [4.5] decan-8-yl } -5- (4-methylphenyl) pyrimidin-4-yl) benzonitrile;

4- [5- (4-methylphenyl) -2- { 9-oxa-3, 7-diazabicyclo [3.3.1] non-3-yl } pyrimidin-4-yl ] benzonitrile; and

4- [5- (4-fluorophenyl) -2- { 9-oxa-3, 7-diazabicyclo [3.3.1] non-3-yl } pyrimidin-4-yl ] benzonitrile;

or a pharmaceutically acceptable salt thereof.

32. A pharmaceutical composition comprising a compound as described in any one of claims 1-31, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

33. Use of a compound as described in any one of claims 1-31, or a pharmaceutically acceptable salt thereof, for the preparation of a pharmaceutical composition for modulating gene transcription in a cell.

34. Use of a compound as described in any one of claims 1-31, or a pharmaceutically acceptable salt thereof, for the manufacture of a pharmaceutical composition for treating cancer in a patient in need thereof.

35. The use of claim 34, wherein the cancer is prostate cancer, breast cancer, bladder cancer, lung cancer, melanoma, or acute myeloid leukemia.